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Dr. Honglin Luo
University of British Columbia

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0 Lung Cancer
0 Viral Pathogenesis
0 Oncolytic Virus
0 Breast cancer treatment
0 Enteroviruses

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Enteroviruses
Viral Pathogenesis
Oncolytic Virus
Lung Cancer

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Journal article
Published: 20 August 2021 in Cells
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Coxsackievirus B3 (CVB3), an enterovirus (EV) in the family of Picornaviridae, is a global human pathogen for which effective antiviral treatments and vaccines are lacking. Previous research demonstrated that EV-D68 downregulated the membrane fusion protein SNAP47 (synaptosome associated protein 47) and SNAP47 promoted EV-D68 replication via regulating autophagy. In the current study, we investigated the interplay between CVB3 and cellular SNAP47 using HEK293T/HeLa cell models. We showed that, upon CVB3 infection, protein levels of SNAP47 decreased independent of the activity of virus-encoded proteinase 3C. We further demonstrated that the depletion of SNAP47 inhibited CVB3 infection, indicating a pro-viral function of SNAP47. Moreover, we found that SNAP47 co-localizes with the autophagy-related protein ATG14 on the cellular membrane fractions together with viral capsid protein VP1, and expression of SNAP47 or ATG14 enhanced VP1 conjugation. Finally, we revealed that disulfide interactions had an important role in strengthening VP1 conjugation. Collectively, our study elucidated a mechanism by which SNAP47 and ATG14 promoted CVB3 propagation through facilitating viral capsid assembly.

ACS Style

Pinhao Xiang; Yasir Mohamud; Honglin Luo. SNAP47 Interacts with ATG14 to Promote VP1 Conjugation and CVB3 Propagation. Cells 2021, 10, 2141 .

AMA Style

Pinhao Xiang, Yasir Mohamud, Honglin Luo. SNAP47 Interacts with ATG14 to Promote VP1 Conjugation and CVB3 Propagation. Cells. 2021; 10 (8):2141.

Chicago/Turabian Style

Pinhao Xiang; Yasir Mohamud; Honglin Luo. 2021. "SNAP47 Interacts with ATG14 to Promote VP1 Conjugation and CVB3 Propagation." Cells 10, no. 8: 2141.

Preprint content
Published: 30 July 2021
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Background: Amyotrophic lateral sclerosis (ALS) is a fatalneurodegenerative disease of the motor neuron system associated with both genetic and environmental risk factors.Infection with enteroviruses, including poliovirus and coxsackievirus B3 (CVB3), has been proposed as a possible causal/risk factor for ALSdue to the evidence that enteroviruses can target motor neurons and establish a persistent infection in the central nervous system (CNS), and recent findings that enteroviral infection-induced molecular and pathologicalphenotypes closely resembleALS. However, a causal relationship has not yet been affirmed.Methods:Wild-type C57BL/6J and SOD1G85R ALS mice were intracerebroventricularly infected with a sublethal dose of CVB3 or sham-infected. For a subset of mice, ribavirin (a broad-spectrum anti-RNA viral drug) was given subcutaneously during the acute and/or chronic stage of infection. Following viral infection, general activity and survival were monitored daily for up to week 60. Starting atweek 20 post-infection (PI), motor functions were measured weekly. Mouse brains and/or spinal cords were harvested at day 10 and week 60 PI for histopathological evaluation of neurotoxicity, immunohistochemical staining of viral protein, neuroinflammatory/immune and ALS pathology markers, and NanoString and RT-qPCR analysis of inflammatory gene expression.Results: We found that sublethal infection (mimicking chronic infection) of SOD1G85R ALS mice with CVB3 resulted inearly onset and progressive motor dysfunction, andshortened lifespan, while similar viral infection in C57BL/6J, the background strain of SOD1G85R mice, did not significantly affect motor function and mortality as compared to mock infection within the timeframe of the current study (60 weeksPI).Furthermore, we showed that CVB3 infection led to a significant increase in proinflammatory gene expression and immune cell infiltration and induced ALS-related pathologies (i.e., TDP-43 pathology and neuronal damage) in the CNS of both SOD1G85R and C57BL/6J mice. Finally, wediscovered that early (day 1) but not late (day 15) administration of ribavirincould rescue ALS-like neuropathology and symptoms induced by CVB3 infection.Conclusions: Our study identifies a new risk factor that contributes to early onset and accelerated progression of ALS and offers opportunities for the development of novel targeted therapies.

ACS Style

Honglin Luo; Yuan Chao Xue; Huitao Liu; Yasir Mohamud; Amirhossein Bahreyni; Jingchun Zhang; Neil R Cashman. Sublethal Enteroviral Infection Exacerbates Disease Progression in an ALS Mouse Model. 2021, 1 .

AMA Style

Honglin Luo, Yuan Chao Xue, Huitao Liu, Yasir Mohamud, Amirhossein Bahreyni, Jingchun Zhang, Neil R Cashman. Sublethal Enteroviral Infection Exacerbates Disease Progression in an ALS Mouse Model. . 2021; ():1.

Chicago/Turabian Style

Honglin Luo; Yuan Chao Xue; Huitao Liu; Yasir Mohamud; Amirhossein Bahreyni; Jingchun Zhang; Neil R Cashman. 2021. "Sublethal Enteroviral Infection Exacerbates Disease Progression in an ALS Mouse Model." , no. : 1.

Review
Published: 05 June 2021 in Viruses
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Oncolytic viruses have emerged as a promising strategy for cancer therapy due to their dual ability to selectively infect and lyse tumor cells and to induce systemic anti-tumor immunity. Among various candidate viruses, coxsackievirus group B (CVBs) have attracted increasing attention in recent years. CVBs are a group of small, non-enveloped, single-stranded, positive-sense RNA viruses, belonging to species human Enterovirus B in the genus Enterovirus of the family Picornaviridae. Preclinical studies have demonstrated potent anti-tumor activities for CVBs, particularly type 3, against multiple cancer types, including lung, breast, and colorectal cancer. Various approaches have been proposed or applied to enhance the safety and specificity of CVBs towards tumor cells and to further increase their anti-tumor efficacy. This review summarizes current knowledge and strategies for developing CVBs as oncolytic viruses for cancer virotherapy. The challenges arising from these studies and future prospects are also discussed in this review.

ACS Style

Huitao Liu; Honglin Luo. Development of Group B Coxsackievirus as an Oncolytic Virus: Opportunities and Challenges. Viruses 2021, 13, 1082 .

AMA Style

Huitao Liu, Honglin Luo. Development of Group B Coxsackievirus as an Oncolytic Virus: Opportunities and Challenges. Viruses. 2021; 13 (6):1082.

Chicago/Turabian Style

Huitao Liu; Honglin Luo. 2021. "Development of Group B Coxsackievirus as an Oncolytic Virus: Opportunities and Challenges." Viruses 13, no. 6: 1082.

Microbiology
Published: 04 June 2021 in Frontiers in Microbiology
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Enteroviruses (EVs) usurp the host autophagy pathway for pro-viral functions; however, the consequence of EV-induced diversion of autophagy on organelle quality control is poorly defined. Using coxsackievirus B3 (CVB3) as a model EV, we explored the interplay between EV infection and selective autophagy receptors, i.e., Tax1-binding protein 1/TRAF6-binding protein (T6BP), optineurin (OPTN), and nuclear dot 10 protein 52 (NDP52), known to be involved in regulating the clearance of damaged mitochondria, a process termed as mitophagy. Following CVB3 infection, we showed significant perturbations of the mitochondrial network coincident with degradation of the autophagy receptor protein T6BP, similar phenomenon to what we previously observed on NDP52. Notably, protein levels of OPTN are not altered during early infection and slightly reduced upon late infection. Cell culture studies revealed that T6BP degradation occurs independent of the function of host caspases and viral proteinase 3C, but requires the proteolytic activity of viral proteinase 2A. Further investigation identified the cleavage site on T6BP after the amino acid 621 that separates the C-terminal ubiquitin-binding domain from the other functional domains at the N-terminus. Genetic silencing of T6BP and OPTN results in the attenuation of CVB3 replication, suggesting a pro-viral activity for these two proteins. Finally, functional assessment of cleaved fragments from NDP52 and T6BP revealed abnormal binding affinity and impaired capacity to be recruited to depolarized mitochondria. Collectively, these results suggest that CVB3 targets autophagy receptors to impair selective autophagy.

ACS Style

Yasir Mohamud; Yuan Chao Xue; Huitao Liu; Chen Seng Ng; Amirhossein Bahreyni; Honglin Luo. Autophagy Receptor Protein Tax1-Binding Protein 1/TRAF6-Binding Protein Is a Cellular Substrate of Enteroviral Proteinase. Frontiers in Microbiology 2021, 12, 1 .

AMA Style

Yasir Mohamud, Yuan Chao Xue, Huitao Liu, Chen Seng Ng, Amirhossein Bahreyni, Honglin Luo. Autophagy Receptor Protein Tax1-Binding Protein 1/TRAF6-Binding Protein Is a Cellular Substrate of Enteroviral Proteinase. Frontiers in Microbiology. 2021; 12 ():1.

Chicago/Turabian Style

Yasir Mohamud; Yuan Chao Xue; Huitao Liu; Chen Seng Ng; Amirhossein Bahreyni; Honglin Luo. 2021. "Autophagy Receptor Protein Tax1-Binding Protein 1/TRAF6-Binding Protein Is a Cellular Substrate of Enteroviral Proteinase." Frontiers in Microbiology 12, no. : 1.

Journal article
Published: 24 May 2021 in Journal of Virology
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Enteroviruses are common human pathogens, including those that cause myocarditis (coxsackievirus B3 [CVB3]), poliomyelitis (poliovirus), and hand, foot, and mouth disease (enterovirus 71). Understanding the virus-host interaction is crucial for developing means of treating and preventing diseases caused by these pathogens.

ACS Style

Yuan Chao Xue; Chen Seng Ng; Yasir Mohamud; Gabriel Fung; Huitao Liu; Amirhossein Bahreyni; Jingchun Zhang; Honglin Luo. FUS/TLS Suppresses Enterovirus Replication and Promotes Antiviral Innate Immune Responses. Journal of Virology 2021, 95, 1 .

AMA Style

Yuan Chao Xue, Chen Seng Ng, Yasir Mohamud, Gabriel Fung, Huitao Liu, Amirhossein Bahreyni, Jingchun Zhang, Honglin Luo. FUS/TLS Suppresses Enterovirus Replication and Promotes Antiviral Innate Immune Responses. Journal of Virology. 2021; 95 (12):1.

Chicago/Turabian Style

Yuan Chao Xue; Chen Seng Ng; Yasir Mohamud; Gabriel Fung; Huitao Liu; Amirhossein Bahreyni; Jingchun Zhang; Honglin Luo. 2021. "FUS/TLS Suppresses Enterovirus Replication and Promotes Antiviral Innate Immune Responses." Journal of Virology 95, no. 12: 1.

Research paper
Published: 10 March 2021 in Autophagy
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Coxsackievirus B3 (CVB3) is a prevalent etiological agent for viral myocarditis and neurological disorders, particularly in infants and young children. Virus-encoded proteinases have emerged as cytopathic factors that contribute to disease pathogenesis in part through targeting the cellular recycling machinery of autophagy. Although it is appreciated that CVB3 can usurp cellular macroautophagy/autophagy for pro-viral functions, the precise mechanisms by which viral proteinases disrupt autophagy remain incompletely understood. Here we identified TFEB (transcription factor EB), a master regulator of autophagy and lysosome biogenesis, as a novel target of CVB3 proteinase 3 C. Time-course infections uncovered a significant loss of full-length TFEB and the emergence of a lower-molecular mass (~63 kDa) fragment. Cellular and in vitro cleavage assays revealed the involvement of viral proteinase 3 C in the proteolytic processing of TFEB, while site-directed mutagenesis identified the site of cleavage after glutamine 60. Assessment of TFEB transcriptional activity using a reporter construct discovered a loss of function of the cleavage fragment despite nuclear localization and retaining of the ability of DNA and protein binding. Furthermore, we showed that CVB3 infection was also able to trigger cleavage-independent nuclear translocation of TFEB that relied on the serine-threonine phosphatase PPP3/calcineurin. Finally, we demonstrated that both TFEB and TFEB [Δ60] serve roles in viral egress albeit through differing mechanisms. Collectively, this study reveals that CVB3 targets TFEB for proteolytic processing to disrupt host lysosomal function and enhance viral infection. Abbreviations:ACTB: actin beta; CLEAR: coordinated lysosomal enhancement and regulation; CVB3: coxsackievirus B3; DAPI: 4′,6-diamidino-2-phenylindole; GFP: green fluorescent protein; LAMP1: lysosomal associated membrane protein 1; LTR: LysoTracker Red; PPP3/calcineurin: protein phosphatase 3; PPP3CA: protein phosphatase 3 catalytic subunit A; p-TFEB: phospho-Ser211 TFEB; si-CON: scramble control siRNA; TFEB: transcription factor EB; TFEB [Δ60]: TFEB cleavage fragment that lacks the first 60 amino acids; VP1: viral capsid protein 1

ACS Style

Yasir Mohamud; Hui Tang; Yuan Chao Xue; Huitao Liu; Chen Seng Ng; Amirhossein Bahreyni; Honglin Luo. Coxsackievirus B3 targets TFEB to disrupt lysosomal function. Autophagy 2021, 1 -15.

AMA Style

Yasir Mohamud, Hui Tang, Yuan Chao Xue, Huitao Liu, Chen Seng Ng, Amirhossein Bahreyni, Honglin Luo. Coxsackievirus B3 targets TFEB to disrupt lysosomal function. Autophagy. 2021; ():1-15.

Chicago/Turabian Style

Yasir Mohamud; Hui Tang; Yuan Chao Xue; Huitao Liu; Chen Seng Ng; Amirhossein Bahreyni; Honglin Luo. 2021. "Coxsackievirus B3 targets TFEB to disrupt lysosomal function." Autophagy , no. : 1-15.

Correction
Published: 25 January 2021 in Molecular Therapy - Oncolytics
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(Mol. Ther. Oncolytics 16, 207–218; March 27, 2020)

ACS Style

Huitao Liu; Yuan Chao Xue; Haoyu Deng; Yasir Mohamud; Chen Seng Ng; Axel Chu; Chinten James Lim; William W. Lockwood; William W.G. Jia; Honglin Luo. MicroRNA modification of coxsackievirus B3 decreases its toxicity, while retaining oncolytic potency against lung cancer. Molecular Therapy - Oncolytics 2021, 20, 1 -2.

AMA Style

Huitao Liu, Yuan Chao Xue, Haoyu Deng, Yasir Mohamud, Chen Seng Ng, Axel Chu, Chinten James Lim, William W. Lockwood, William W.G. Jia, Honglin Luo. MicroRNA modification of coxsackievirus B3 decreases its toxicity, while retaining oncolytic potency against lung cancer. Molecular Therapy - Oncolytics. 2021; 20 ():1-2.

Chicago/Turabian Style

Huitao Liu; Yuan Chao Xue; Haoyu Deng; Yasir Mohamud; Chen Seng Ng; Axel Chu; Chinten James Lim; William W. Lockwood; William W.G. Jia; Honglin Luo. 2021. "MicroRNA modification of coxsackievirus B3 decreases its toxicity, while retaining oncolytic potency against lung cancer." Molecular Therapy - Oncolytics 20, no. : 1-2.

Short communication
Published: 08 January 2021 in Biochemical and Biophysical Research Communications
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The ongoing pandemic of COVID-19 alongside the outbreaks of SARS in 2003 and MERS in 2012 underscore the significance to understand betacoronaviruses as a global health challenge. SARS-CoV-2, the etiological agent for COVID-19, has infected over 50 million individuals’ worldwide with more than ∼1 million fatalities. Autophagy modulators have emerged as potential therapeutic candidates against SARS-CoV-2 but recent clinical setbacks urge for better understanding of viral subversion of autophagy. Using MHV-A59 as a model betacoronavirus, time-course infections revealed significant loss in the protein level of ULK1, a canonical autophagy-regulating kinase, and the concomitant appearance of a possible cleavage fragment. To investigate whether virus-encoded proteases target ULK1, we conducted in-vitro and cellular cleavage assays and identified ULK1 as a novel bona fide substrate of SARS-CoV-2 papain-like protease (PLpro). Mutagenesis studies discovered that ULK1 is cleaved at a conserved PLpro recognition sequence (LGGG) after G499, separating its N-terminal kinase domain from a C-terminal substrate recognition region. Over-expression of SARS-CoV-2 PLpro is sufficient to impair starvation-induced autophagy and disrupt formation of ULK1-ATG13 complex. Finally, we demonstrated a dual role for ULK1 in MHV-A59 replication, serving a pro-viral functions during early replication that is inactivated at late stages of infection. In conclusion, our study identified a new mechanism by which PLpro of betacoronaviruses induces viral pathogenesis by targeting cellular autophagy.

ACS Style

Yasir Mohamud; Yuan Chao Xue; Huitao Liu; Chen Seng Ng; Amirhossein Bahreyni; Eric Jan; Honglin Luo. The papain-like protease of coronaviruses cleaves ULK1 to disrupt host autophagy. Biochemical and Biophysical Research Communications 2021, 540, 75 -82.

AMA Style

Yasir Mohamud, Yuan Chao Xue, Huitao Liu, Chen Seng Ng, Amirhossein Bahreyni, Eric Jan, Honglin Luo. The papain-like protease of coronaviruses cleaves ULK1 to disrupt host autophagy. Biochemical and Biophysical Research Communications. 2021; 540 ():75-82.

Chicago/Turabian Style

Yasir Mohamud; Yuan Chao Xue; Huitao Liu; Chen Seng Ng; Amirhossein Bahreyni; Eric Jan; Honglin Luo. 2021. "The papain-like protease of coronaviruses cleaves ULK1 to disrupt host autophagy." Biochemical and Biophysical Research Communications 540, no. : 75-82.

Review
Published: 07 January 2021 in Reviews in Medical Virology
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Severe acute respiratory syndrome coronavirus‐2 is the etiological agent of the ongoing pandemic of coronavirus disease‐2019, a multi‐organ disease that has triggered an unprecedented global health and economic crisis. The virally encoded 3C‐like protease (3CLpro), which is named after picornaviral 3C protease (3Cpro) due to their similarities in substrate recognition and enzymatic activity, is essential for viral replication and has been considered as the primary drug target. However, information regarding the cellular substrates of 3CLpro and its interaction with the host remains scarce, though recent work has begun to shape our understanding more clearly. Here we summarized and compared the mechanisms by which picornaviruses and coronaviruses have evolved to evade innate immune surveillance, with a focus on the established role of 3Cpro in this process. Through this comparison, we hope to highlight the potential action and mechanisms that are conserved and shared between 3Cpro and 3CLpro. In this review, we also briefly discussed current advances in the development of broad‐spectrum antivirals targeting both 3Cpro and 3CLpro.

ACS Style

Chen Seng Ng; Christopher C. Stobart; Honglin Luo. Innate immune evasion mediated by picornaviral 3C protease: Possible lessons for coronaviral 3C‐like protease? Reviews in Medical Virology 2021, e2206 .

AMA Style

Chen Seng Ng, Christopher C. Stobart, Honglin Luo. Innate immune evasion mediated by picornaviral 3C protease: Possible lessons for coronaviral 3C‐like protease? Reviews in Medical Virology. 2021; ():e2206.

Chicago/Turabian Style

Chen Seng Ng; Christopher C. Stobart; Honglin Luo. 2021. "Innate immune evasion mediated by picornaviral 3C protease: Possible lessons for coronaviral 3C‐like protease?" Reviews in Medical Virology , no. : e2206.

Review
Published: 09 December 2020 in Journal of Nanobiotechnology
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Breast cancer continues to be the most frequently diagnosed malignancy among women, putting their life in jeopardy. Cancer immunotherapy is a novel approach with the ability to boost the host immune system to recognize and eradicate cancer cells with high selectivity. As a promising treatment, immunotherapy can not only eliminate the primary tumors, but also be proven to be effective in impeding metastasis and recurrence. However, the clinical application of cancer immunotherapy has faced some limitations including generating weak immune responses due to inadequate delivery of immunostimulants to the immune cells as well as uncontrolled modulation of immune system, which can give rise to autoimmunity and nonspecific inflammation. Growing evidence has suggested that nanotechnology may meet the needs of current cancer immunotherapy. Advanced biomaterials such as nanoparticles afford a unique opportunity to maximize the efficiency of immunotherapy and significantly diminish their toxic side-effects. Here we discuss recent advancements that have been made in nanoparticle-involving breast cancer immunotherapy, varying from direct activation of immune systems through the delivery of tumor antigens and adjuvants to immune cells to altering immunosuppression of tumor environment and combination with other conventional therapies.

ACS Style

Amirhossein Bahreyni; Yasir Mohamud; Honglin Luo. Emerging nanomedicines for effective breast cancer immunotherapy. Journal of Nanobiotechnology 2020, 18, 1 -14.

AMA Style

Amirhossein Bahreyni, Yasir Mohamud, Honglin Luo. Emerging nanomedicines for effective breast cancer immunotherapy. Journal of Nanobiotechnology. 2020; 18 (1):1-14.

Chicago/Turabian Style

Amirhossein Bahreyni; Yasir Mohamud; Honglin Luo. 2020. "Emerging nanomedicines for effective breast cancer immunotherapy." Journal of Nanobiotechnology 18, no. 1: 1-14.

Review
Published: 03 December 2020 in Cancers
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Short interfering RNAs (siRNAs) have provided novel insights into the field of cancer treatment in light of their ability to specifically target and silence cancer-associated genes. In recent years, numerous studies focus on determining genes that actively participate in tumor formation, invasion, and metastasis in order to establish new targets for cancer treatment. In spite of great advances in designing various siRNAs with diverse targets, efficient delivery of siRNAs to cancer cells is still the main challenge in siRNA-mediated cancer treatment. Recent advancements in the field of nanotechnology and nanomedicine hold great promise to meet this challenge. This review focuses on recent findings in cancer-associated genes and the application of siRNAs to successfully silence them in prostate cancer, as well as recent progress for effectual delivery of siRNAs to cancer cells.

ACS Style

Amirhossein Bahreyni; Honglin Luo. Advances in Targeting Cancer-Associated Genes by Designed siRNA in Prostate Cancer. Cancers 2020, 12, 3619 .

AMA Style

Amirhossein Bahreyni, Honglin Luo. Advances in Targeting Cancer-Associated Genes by Designed siRNA in Prostate Cancer. Cancers. 2020; 12 (12):3619.

Chicago/Turabian Style

Amirhossein Bahreyni; Honglin Luo. 2020. "Advances in Targeting Cancer-Associated Genes by Designed siRNA in Prostate Cancer." Cancers 12, no. 12: 3619.

Journal article
Published: 04 November 2020 in Scientific Reports
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Coxsackievirus B3 (CVB3) is a single-stranded positive RNA virus that usurps cellular machinery, including the evolutionarily anti-viral autophagy pathway, for productive infections. Despite the emergence of double-membraned autophagosome-like vesicles during CVB3 infection, very little is known about the mechanism of autophagy initiation. In this study, we investigated the role of established autophagy factors in the initiation of CVB3-induced autophagy. Using siRNA-mediated gene-silencing and CRISPR-Cas9-based gene-editing in culture cells, we discovered that CVB3 bypasses the ULK1/2 and PI3K complexes to trigger autophagy. Moreover, we found that CVB3-induced LC3 lipidation occurred independent of WIPI2 and the transmembrane protein ATG9 but required components of the late-stage ubiquitin-like ATG conjugation system including ATG5 and ATG16L1. Remarkably, we showed the canonical autophagy factor ULK1 was cleaved through the catalytic activity of the viral proteinase 3C. Mutagenesis experiments identified the cleavage site of ULK1 after Q524, which separates its N-terminal kinase domain from C-terminal substrate binding domain. Finally, we uncovered PI4KIIIβ (a PI4P kinase), but not PI3P or PI5P kinases as requisites for CVB3-induced LC3 lipidation. Taken together, our studies reveal that CVB3 initiates a non-canonical form of autophagy that bypasses ULK1/2 and PI3K signaling pathways to ultimately converge on PI4KIIIβ- and ATG5–ATG12–ATG16L1 machinery.

ACS Style

Yasir Mohamud; Junyan Shi; Hui Tang; Pinhao Xiang; Yuan Chao Xue; Huitao Liu; Chen Seng Ng; Honglin Luo. Coxsackievirus infection induces a non-canonical autophagy independent of the ULK and PI3K complexes. Scientific Reports 2020, 10, 1 -14.

AMA Style

Yasir Mohamud, Junyan Shi, Hui Tang, Pinhao Xiang, Yuan Chao Xue, Huitao Liu, Chen Seng Ng, Honglin Luo. Coxsackievirus infection induces a non-canonical autophagy independent of the ULK and PI3K complexes. Scientific Reports. 2020; 10 (1):1-14.

Chicago/Turabian Style

Yasir Mohamud; Junyan Shi; Hui Tang; Pinhao Xiang; Yuan Chao Xue; Huitao Liu; Chen Seng Ng; Honglin Luo. 2020. "Coxsackievirus infection induces a non-canonical autophagy independent of the ULK and PI3K complexes." Scientific Reports 10, no. 1: 1-14.

Preprint content
Published: 25 October 2020
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The ongoing pandemic of COVID-19 alongside the outbreaks of SARS in 2003 and MERS in 2012 underscore the significance to understand betacoronaviruses as a global health challenge. SARS-CoV-2, the etiological agent for COVID-19, has infected more than 29 million individuals worldwide with nearly ~1 million fatalities. Understanding how SARS-CoV-2 initiates viral pathogenesis is of the utmost importance for development of antiviral drugs. Autophagy modulators have emerged as potential therapeutic candidates against SARS-CoV-2 but recent clinical setbacks underline the urgent need for better understanding the mechanism of viral subversion of autophagy. Using murine hepatitis virus-A59 (MHV-A59) as a model betacoronavirus, time-course infections revealed a significant loss in the protein level of ULK1, a canonical autophagy regulating serine-threonine kinase, and the concomitant appearance of a possible cleavage fragment. To investigate whether virus-encoded proteases target this protein, we conducted in vitro and cellular cleavage assays and identified ULK1 as a novel bona fide substrate of SARS-CoV-2 papain-like protease (PLpro). Mutagenesis studies discovered that ULK1 is cleaved at a conserved PLpro recognition sequence (LGGG) after G499, separating its N-terminal kinase domain from the C-terminal substrate recognition region. Consistent with this, over-expression of SARS-CoV-2 PLpro is sufficient to impair starvation-induced canonical autophagy and disrupt formation of ULK1-ATG13 complex. Finally, we demonstrated a dual role for ULK1 in MHV-A59 replication, serving a pro-viral functions during early replication that is inactivated at late stages of infection. In conclusion, our study identified a new mechanism by which PLpro of betacoronaviruses induces viral pathogenesis by targeting cellular autophagic pathway.

ACS Style

Yasir Mohamud; Yuan Chao Xue; Huitao Liu; Chen Seng Ng; Amirhossein Bahreyni; Eric Jan; Honglin Luo. The papain-like protease of coronaviruses cleaves ULK1 to disrupt host autophagy. 2020, 1 .

AMA Style

Yasir Mohamud, Yuan Chao Xue, Huitao Liu, Chen Seng Ng, Amirhossein Bahreyni, Eric Jan, Honglin Luo. The papain-like protease of coronaviruses cleaves ULK1 to disrupt host autophagy. . 2020; ():1.

Chicago/Turabian Style

Yasir Mohamud; Yuan Chao Xue; Huitao Liu; Chen Seng Ng; Amirhossein Bahreyni; Eric Jan; Honglin Luo. 2020. "The papain-like protease of coronaviruses cleaves ULK1 to disrupt host autophagy." , no. : 1.

Review article
Published: 29 May 2020 in Frontiers in Molecular Neuroscience
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Genetic analyses of patients with amyotrophic lateral sclerosis (ALS) have revealed a strong association between mutations in genes encoding many RNA-binding proteins (RBPs), including TARDBP, FUS, hnRNPA1, hnRNPA2B1, MATR3, ATXN2, TAF15, TIA-1, and EWSR1, and disease onset/progression. RBPs are a group of evolutionally conserved proteins that participate in multiple steps of RNA metabolism, including splicing, polyadenylation, mRNA stability, localization, and translation. Dysregulation of RBPs, as a consequence of gene mutations, impaired nucleocytoplasmic trafficking, posttranslational modification (PTM), aggregation, and sequestration by abnormal RNA foci, has been shown to be involved in neurodegeneration and the development of ALS. While the exact mechanism by which dysregulated RBPs contribute to ALS remains elusive, emerging evidence supports the notion that both a loss of function and/or a gain of toxic function of these ALS-linked RBPs play a significant role in disease pathogenesis through facilitating abnormal protein interaction, causing aberrant RNA metabolism, and by disturbing ribonucleoprotein granule dynamics and phase transition. In this review article, we summarize the current knowledge on the molecular mechanism by which RBPs are dysregulated and the influence of defective RBPs on cellular homeostasis during the development of ALS. The strategies of ongoing clinical trials targeting RBPs and/or relevant processes are also discussed in the present review.

ACS Style

Yuan Chao Xue; Chen Seng Ng; Pinhao Xiang; Huitao Liu; Kevin Zhang; Yasir Mohamud; Honglin Luo. Dysregulation of RNA-Binding Proteins in Amyotrophic Lateral Sclerosis. Frontiers in Molecular Neuroscience 2020, 13, 78 .

AMA Style

Yuan Chao Xue, Chen Seng Ng, Pinhao Xiang, Huitao Liu, Kevin Zhang, Yasir Mohamud, Honglin Luo. Dysregulation of RNA-Binding Proteins in Amyotrophic Lateral Sclerosis. Frontiers in Molecular Neuroscience. 2020; 13 ():78.

Chicago/Turabian Style

Yuan Chao Xue; Chen Seng Ng; Pinhao Xiang; Huitao Liu; Kevin Zhang; Yasir Mohamud; Honglin Luo. 2020. "Dysregulation of RNA-Binding Proteins in Amyotrophic Lateral Sclerosis." Frontiers in Molecular Neuroscience 13, no. : 78.

Journal article
Published: 07 February 2020 in Cell Death & Differentiation
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Host nucleases are implicated in antiviral response through the processing of pathogen-derived nucleic acids. Among many host RNases, decapping enzymes DCP1 and 2, and 5′→3′ exonuclease XRN1, which are components of the RNA decay machinery, have been extensively studied in prokaryotes, plants, and invertebrates but less so in mammalian systems. As a result, the implication of XRN1 and DCPs in viral replication, in particular, the spatio-temporal dynamics during RNA viral infections remains elusive. Here, we highlight that XRN1 and DCPs play a critical role in limiting several groups of RNA viral infections. This antiviral activity was not obvious in wild-type cells but clearly observed in type I interferon (IFN-I)-deficient cells. Mechanistically, infection with RNA viruses induced the enrichment of XRN1 and DCPs in viral replication complexes (vRCs), hence forming distinct cytoplasmic aggregates. These aggregates served as sites for direct interaction between XRN1, DCP1/2, and viral ribonucleoprotein that contains viral RNA (vRNA). Although these XRN1-DCP1/2-vRC-containing foci resemble antiviral stress granules (SGs) or P-body (PB), they did not colocalize with known SG markers and did not correlate with critical PB functions. Furthermore, the presence of 5′ mono- and 5′ triphosphate structures on vRNA was not required for the formation of XRN1-DCP1/2-vRC-containing foci. On the other hand, single-, double-stranded, and higher-ordered vRNA species play a role but are not deterministic for efficient formation of XRN1-DCP1/2 foci and consequent antiviral activity in a manner proportional to RNA length. These results highlight the mechanism behind the antiviral function of XRN1-DCP1/2 in RNA viral infections independent of IFN-I response, protein kinase R and PB function.

ACS Style

Chen Seng Ng; Dacquin Kasumba; Takashi Fujita; Honglin Luo. Spatio-temporal characterization of the antiviral activity of the XRN1-DCP1/2 aggregation against cytoplasmic RNA viruses to prevent cell death. Cell Death & Differentiation 2020, 27, 2363 -2382.

AMA Style

Chen Seng Ng, Dacquin Kasumba, Takashi Fujita, Honglin Luo. Spatio-temporal characterization of the antiviral activity of the XRN1-DCP1/2 aggregation against cytoplasmic RNA viruses to prevent cell death. Cell Death & Differentiation. 2020; 27 (8):2363-2382.

Chicago/Turabian Style

Chen Seng Ng; Dacquin Kasumba; Takashi Fujita; Honglin Luo. 2020. "Spatio-temporal characterization of the antiviral activity of the XRN1-DCP1/2 aggregation against cytoplasmic RNA viruses to prevent cell death." Cell Death & Differentiation 27, no. 8: 2363-2382.

Journal article
Published: 20 January 2020 in Molecular Therapy - Oncolytics
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We recently discovered that coxsackievirus B3 (CVB3) is a potent oncolytic virus against KRAS mutant lung adenocarcinoma. Nevertheless, the evident toxicity restricts the use of wild-type (WT)-CVB3 for cancer therapy. The current study aims to engineer the CVB3 to decrease its toxicity and to extend our previous research to determine its safety and efficacy in treating TP53/RB1 mutant small-cell lung cancer (SCLC). A microRNA-modified CVB3 (miR-CVB3) was generated via inserting multiple copies of tumor-suppressive miR-145/miR-143 target sequences into the viral genome. In vitro experiments revealed that miR-CVB3 retained the ability to infect and lyse KRAS mutant lung adenocarcinoma and TP53/RB1-mutant SCLC cells, but with a markedly reduced cytotoxicity toward cardiomyocytes. In vivo study using a TP53/RB1-mutant SCLC xenograft model demonstrated that a single dose of miR-CVB3 via systemic administration resulted in a significant tumor regression. Most strikingly, mice treated with miR-CVB3 exhibited greatly attenuated cardiotoxicities and decreased viral titers compared to WT-CVB3-treated mice. Collectively, we generated a recombinant CVB3 that is powerful in destroying both KRAS mutant lung adenocarcinoma and TP53/RB1-mutant SCLC, with a negligible toxicity toward normal tissues. Future investigation is needed to address the issue of genome instability of miR-CVB3, which was observed in ~40% of mice after a prolonged treatment.

ACS Style

Huitao Liu; Yuan Chao Xue; Haoyu Deng; Yasir Mohamud; Chen Seng Ng; Axel Chu; Chinten James Lim; William W. Lockwood; William W.G. Jia; Honglin Luo. MicroRNA Modification of Coxsackievirus B3 Decreases Its Toxicity, while Retaining Oncolytic Potency against Lung Cancer. Molecular Therapy - Oncolytics 2020, 16, 207 -218.

AMA Style

Huitao Liu, Yuan Chao Xue, Haoyu Deng, Yasir Mohamud, Chen Seng Ng, Axel Chu, Chinten James Lim, William W. Lockwood, William W.G. Jia, Honglin Luo. MicroRNA Modification of Coxsackievirus B3 Decreases Its Toxicity, while Retaining Oncolytic Potency against Lung Cancer. Molecular Therapy - Oncolytics. 2020; 16 ():207-218.

Chicago/Turabian Style

Huitao Liu; Yuan Chao Xue; Haoyu Deng; Yasir Mohamud; Chen Seng Ng; Axel Chu; Chinten James Lim; William W. Lockwood; William W.G. Jia; Honglin Luo. 2020. "MicroRNA Modification of Coxsackievirus B3 Decreases Its Toxicity, while Retaining Oncolytic Potency against Lung Cancer." Molecular Therapy - Oncolytics 16, no. : 207-218.

Journal article
Published: 23 July 2019 in Molecular Therapy - Oncolytics
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KRAS mutant (KRAS mut) lung adenocarcinoma is a refractory cancer without available targeted therapy. The current study explored the possibility to develop coxsackievirus type B3 (CVB3) as an oncolytic agent for the treatment of KRAS mut lung adenocarcinoma. In cultured cells, we discovered that CVB3 selectively infects and lyses KRAS mut lung adenocarcinoma cells (A549, H2030, and H23), while sparing normal lung epithelial cells (primary, BEAS2B, HPL1D, and 1HAEo) and EGFR mut lung adenocarcinoma cells (HCC4006, PC9, H3255, and H1975). Using stable cells expressing a single driver mutation of either KRAS G12V or EGFR L858R in normal lung epithelial cells (HPL1D), we further showed that CVB3 specifically kills HPL1D-KRAS G12V cells with minimal harm to HPL1D-EGFR L858R and control cells. Mechanistically, we demonstrated that aberrant activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and compromised type I interferon immune response in KRAS mut lung adenocarcinoma cells serve as key factors contributing to the sensitivity to CVB3-induced cytotoxicity. Lastly, we conducted in vivo xenograft studies using two immunocompromised mouse models. Our results revealed that intratumoral injection of CVB3 results in a marked tumor regression of KRAS mut lung adenocarcinoma in both non-obese diabetic (NOD) severe combined immunodeficiency (SCID) gamma (NSG) and NOD-SCID xenograft models. Together, our findings suggest that CVB3 is an excellent candidate to be further developed as a targeted therapy for KRAS mut lung adenocarcinoma.

ACS Style

Haoyu Deng; Huitao Liu; Tanya de Silva; Yuanchao Xue; Yasir Mohamud; Chen Seng Ng; Junyan Qu; Jingchun Zhang; William W.G. Jia; William W. Lockwood; Honglin Luo. Coxsackievirus Type B3 Is a Potent Oncolytic Virus against KRAS-Mutant Lung Adenocarcinoma. Molecular Therapy - Oncolytics 2019, 14, 266 -278.

AMA Style

Haoyu Deng, Huitao Liu, Tanya de Silva, Yuanchao Xue, Yasir Mohamud, Chen Seng Ng, Junyan Qu, Jingchun Zhang, William W.G. Jia, William W. Lockwood, Honglin Luo. Coxsackievirus Type B3 Is a Potent Oncolytic Virus against KRAS-Mutant Lung Adenocarcinoma. Molecular Therapy - Oncolytics. 2019; 14 ():266-278.

Chicago/Turabian Style

Haoyu Deng; Huitao Liu; Tanya de Silva; Yuanchao Xue; Yasir Mohamud; Chen Seng Ng; Junyan Qu; Jingchun Zhang; William W.G. Jia; William W. Lockwood; Honglin Luo. 2019. "Coxsackievirus Type B3 Is a Potent Oncolytic Virus against KRAS-Mutant Lung Adenocarcinoma." Molecular Therapy - Oncolytics 14, no. : 266-278.

Review
Published: 03 December 2018 in Virulence
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Enteroviruses (EVs) are the most common human pathogens worldwide. Recent international outbreaks in North America and South East Asia have emphasized the need for more effective anti-viral therapies. As obligate parasites, EVs rely on the host cellular machinery for effective viral propagation. Accumulating evidence has indicated that EVs subvert and disrupt the cellular autophagy pathway to facilitate productive infection, and consequently leading to host pathogenesis. Given that defective autophagy is a common factor in various human diseases, including neurodegeneration, cardiomyopathy, and metabolic disorders, a clear understanding of the relationship between EV infection and autophagy is warranted. In this review, we highlight recent advances in understanding the molecular mechanisms by which EVs exploit the autophagy pathway during different steps of viral life cycle, from entry, replication, and maturation to release. We also provide an overview of recent progress in EV subversion of the autophagy for immune evasion.

ACS Style

Yasir Mohamud; Honglin Luo. The Intertwined Life Cycles of Enterovirus and Autophagy. Virulence 2018, 10, 470 -480.

AMA Style

Yasir Mohamud, Honglin Luo. The Intertwined Life Cycles of Enterovirus and Autophagy. Virulence. 2018; 10 (1):470-480.

Chicago/Turabian Style

Yasir Mohamud; Honglin Luo. 2018. "The Intertwined Life Cycles of Enterovirus and Autophagy." Virulence 10, no. 1: 470-480.

Journal article
Published: 01 December 2018 in The American Journal of Pathology
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(1) Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that primarily affects motor neurons in the cerebral cortex, brainstems, and spinal cord, leading to progressive paralysis and eventual death. About 95% of all ALS cases are sporadic without known causes. Enteroviruses have been suspected to play a role in ALS due to their ability to target motor neurons and cause muscle weakness and paralysis. I vitro enteroviral infection results in cytoplasmic aggregation and cleavage of transactive response DNA binding protein-43 (TDP-43), a pathological hallmark of ALS. However, whether enteroviral infection can induce ALS-like pathologies in vivo remains to be characterized. In this study, neonatal BALB/C mice were intracranially inoculated with either a recombinant coxsackievirus B3 expressing enhanced GFP or mock-infected for 2, 5, 10, 30, and 90 days. Histological and imunohistochemical analysis of brain tissues demonstrated sustained inflammation (microglia and astrogliosis) and lesions in multiple regions of the brain (hippocampus, cerebral cortex, striatum, olfactory bulb, and putamen) in parallel with virus detection as early as two days for up to 90 days post-infection. Most notably, ALS-like pathologies, including cytoplasmic mislocalization of TDP-43, p62-, and ubiquitin-positive inclusions, were observed in the areas of infection. These data provide the first pathological evidence supporting a possible link between enteroviral infection and ALS.

ACS Style

Yuan Chao Xue; Chelsea M. Ruller; Gabriel Fung; Yasir Mohamud; Haoyu Deng; Huitao Liu; Jingchun Zhang; Ralph Feuer; Honglin Luo. Enteroviral Infection Leads to Transactive Response DNA-Binding Protein 43 Pathology in Vivo. The American Journal of Pathology 2018, 188, 2853 -2862.

AMA Style

Yuan Chao Xue, Chelsea M. Ruller, Gabriel Fung, Yasir Mohamud, Haoyu Deng, Huitao Liu, Jingchun Zhang, Ralph Feuer, Honglin Luo. Enteroviral Infection Leads to Transactive Response DNA-Binding Protein 43 Pathology in Vivo. The American Journal of Pathology. 2018; 188 (12):2853-2862.

Chicago/Turabian Style

Yuan Chao Xue; Chelsea M. Ruller; Gabriel Fung; Yasir Mohamud; Haoyu Deng; Huitao Liu; Jingchun Zhang; Ralph Feuer; Honglin Luo. 2018. "Enteroviral Infection Leads to Transactive Response DNA-Binding Protein 43 Pathology in Vivo." The American Journal of Pathology 188, no. 12: 2853-2862.

Journal article
Published: 28 August 2018 in Cell Death & Differentiation
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Cell autonomous immunity is the ability of individual cells to initiate a first line of host defense against invading microbes, such as viruses. Autophagy receptors, a diverse family of multivalent proteins, play a key role in this host response by detecting, sequestering, and eliminating virus in a process termed virophagy. To counteract this, positive-stranded RNA viruses, such as enteroviruses, have evolved strategies to circumvent the host autophagic machinery in an effort to promote viral propagation; however, the underlying mechanisms remain largely unclear. Here we studied the interaction between coxsackievirus B3 (CVB3) and the autophagy receptor SQSTM1 (sequestosome 1)/p62 and CALCOCO2/NDP52 (calcium binding and coiled-coil domain-containing protein 2/nuclear dot 10 protein 52). We demonstrated that SQSTM1 and CALCOCO2 differentially regulate CVB3 infection. We showed that knockdown of SQSTM1 causes increased viral protein production and elevated viral titers, whereas depletion of CALCOCO2 results in a significant inhibition of viral growth. Both receptors appear to have a role in virophagy through direct interaction with the viral capsid protein VP1 that undergoes ubiquitination during infection. Further investigation of the proviral mechanism of CALCOCO2 revealed that CALCOCO2, but not SQSTM1, suppresses the antiviral type I interferon signaling by promoting autophagy-mediated degradation of the mitochondrial antiviral signaling (MAVS) protein. Moreover, we demonstrated that viral proteinase 2A-mediated cleavage of SQSTM1 at glycine 241 impairs its capacity to associate with viral capsid, whereas cleavage of CALCOCO2 by viral proteinase 3C at glutamine 139, generates a stable C-terminal fragment that retains the proviral function of full-length CALCOCO2. Altogether, our study reveals a mechanism by which CVB3 targets selective autophagy receptors to evade host virophagy.

ACS Style

Yasir Mohamud; Junyan Qu; Yuan Chao Xue; Huitao Liu; Haoyu Deng; Honglin Luo. CALCOCO2/NDP52 and SQSTM1/p62 differentially regulate coxsackievirus B3 propagation. Cell Death & Differentiation 2018, 26, 1062 -1076.

AMA Style

Yasir Mohamud, Junyan Qu, Yuan Chao Xue, Huitao Liu, Haoyu Deng, Honglin Luo. CALCOCO2/NDP52 and SQSTM1/p62 differentially regulate coxsackievirus B3 propagation. Cell Death & Differentiation. 2018; 26 (6):1062-1076.

Chicago/Turabian Style

Yasir Mohamud; Junyan Qu; Yuan Chao Xue; Huitao Liu; Haoyu Deng; Honglin Luo. 2018. "CALCOCO2/NDP52 and SQSTM1/p62 differentially regulate coxsackievirus B3 propagation." Cell Death & Differentiation 26, no. 6: 1062-1076.