Oxysterol-binding protein like protein 3 (OSBPL3) has been shown involving in the development of several human cancers. However, the relationship between OSBPL3 and colorectal cancer (CRC), particularly the role of OSBPL3 in the proliferation, invasion and metastasis of CRC remains unclear. In this study, we investigated the role of OSBPL3 in CRC and found that its expression was significantly higher in CRC tissues than that in normal tissues. In addition, high expression of OSBPL3 was closely related to poor differentiation, advanced TNM stage and poor prognosis of CRC. Further experiments showed that over-expression of OSBPL3 promoted the proliferation, invasion and metastasis of CRC in vitro and in vivo models. Moreover, we revealed that OSBPL3 promoted CRC progression through activation of RAS signaling pathway. Furthermore, we demonstrated that hypoxia induced factor 1 (HIF-1A) can regulate the expression of OSBPL3 via binding to the hypoxia response element (HRE) in the promoter of OSBPL3. In summary, Upregulation of OSBPL3 by HIF1A promotes colorectal cancer progression through activation of RAS signaling pathway. This novel mechanism provides a comprehensive understanding of both OSBPL3 and the RAS signaling pathway in the progression of CRC and indicates that the HIF1A–OSBPL3–RAS axis is a potential target for early therapeutic intervention in CRC progression.

Pseudorabies virus (PRV) is recognized as one of the most important pathogens of swine and poses a serious threat to the swine industry worldwide. Available commercial vaccines fail to protect against the emergence of new PRV strains. Therefore, the new protein targets against PRV highlight the urgent need for uncovering the molecular determinants of host cellular proteins following PRV infection. Interferon-stimulated gene 15 (ISG15) demonstrates an outstanding antiviral response. However, the molecular mechanism of ISG15 that affects PRV replication is incompletely known. Here, we performed a tandem mass tag (TMT)-based approach to quantitatively identify protein expression changes in PRV-infected ISG15 knockout PK15 (ISG15^−/−-PK15) cells. In total, 4958 proteins were identified by using TMT coupled with LC-MS/MS in this study. In the PRV- and mock-infected groups, 241 differentially expressed proteins (DEPs) were identified, 162 upregulated and 79 downregulated proteins at 24 h post-infection (hpi), among which AFP, Vtn, Hsp40, Herc5, and Mccc1 may play important roles in PRV propagation. To ensure the validity and reliability of the proteomics data, the randomly selected DEPs were verified by RT-qPCR and Western blot analysis, and the results were consistent with the TMT results. Bioinformatics analyses further demonstrated that the DEPs are mainly involved in various biological processes and signaling pathways, such as signal transduction, the digestive system, and the PI3K-AKT pathway. These findings may provide new insight into molecular mechanisms for PRV infection, which is helpful for identifying potential protein targets for antiviral agents.

Type I interferon (IFN) plays an important role in the host defense against viral infection by inducing expression of interferon-stimulated genes (ISGs). In a previous study, we found that porcine interferon-stimulated gene 15 (ISG15) exhibited antiviral activity against PRV in vitro. To further investigate the antiviral function of ISG15 in vivo, we utilized ISG15 knockout (ISG15^-/-) mice in this study. Here, we demonstrate that ISG15^-/- mice were highly susceptible to PRV infection in vivo, as evidenced by a considerably reduced survival rate, enhanced viral replication and severe pathological lesions. However, we observed no significant difference between female and male infected WT and ISG15^-/- mice. Moreover, ISG15^-/- mice displayed attenuated antiviral protection as a result of considerably reduced expression of IFNβ and relevant ISGs during PRV replication. Furthermore, excessive production of proinflammatory cytokines may be closely related to encephalitis and pneumonia. In further studies, we found that the enhanced sensitivity to PRV infection in ISG15^-/- mice might be caused by reduced phosphorylation of STAT1 and STAT2, thereby inhibiting type I IFN-mediated antiviral activity. Based on these findings, we conclude that ISG15 is essential for host type I IFN-mediated antiviral response.

Background/Objectives: Since its emergence in 2019, the rapid spread of SARS-CoV-2 led to the global pandemic. Recent large-scale dengue fever outbreaks overlapped with the COVID-19 pandemic, leading to increased cases of co-infection and posing severe public health risks. Accordingly, the development of effective combined SARS-CoV-2 and dengue virus (DENV) vaccines is necessary to control the spread and prevalence of both viruses. Methods: In this study, we designed Sindbis virus (SINV) replicon-based SARS-CoV-2 and DENV chimeric vaccines using two delivery strategies: DNA-launched self-replicating RNA replicon (DREP) and viral replicon particle (VRP) systems. Results: Cellular and animal experiments confirmed that the vaccines effectively produced viral proteins and elicited strong immunogenicity. These vaccines induced robust immune responses and neutralizing activity against live SARS-CoV-2, DENV1, and DENV2 viruses. In addition, passively transferred sera from BALB/c mice immunized with these vaccines into AG129 mice provided significant protection against lethal DENV2 challenge. The transferred sera protected the mice from physical symptoms, reduced viral loads in the kidney, spleen, liver, and intestine, and prevented DENV2-induced vascular leakage in these tissues. Conclusions: Therefore, combined vaccines based on the SINV replicon system are promising candidates for pandemic control. These results lay a foundation for further development of a safe and effective combination vaccine against SARS-CoV-2 and DENV.