VISA (also known as MAVS, Cardif, IPS-1) is the essential adaptor protein for virus-induced activation of IFN regulatory factors 3 and 7 and production of type I IFNs. Understanding the regulatory mechanisms for VISA will provide detailed insights into the positive or negative regulation of innate immune responses. In this study, we identified Smad ubiquitin regulatory factor (Smurf) 2, one of the Smad ubiquitin regulator factor proteins, as an important negative regulator of virus-triggered type I IFN signaling, which targets at the VISA level. Overexpression of Smurf2 inhibits virus-induced IFN-β and IFN-stimulated response element activation. The E3 ligase defective mutant Smurf2/C716A loses the ability to suppress virus-induced type I IFN signaling, suggesting that the negative regulation is dependent on the ubiquitin E3 ligase activity of Smurf2. Further studies demonstrated that Smurf2 interacted with VISA and targeted VISA for K48-linked ubiquitination, which promoted the degradation of VISA. Consistently, knockout or knockdown of Smurf2 expression therefore promoted antiviral signaling, which was correlated with the increase in protein stability of VISA. Our findings suggest that Smurf2 is an important nonredundant negative regulator of virus-triggered type I IFN signaling by targeting VISA for K48-linked ubiquitination and degradation.

The inflammasome is an important multiprotein complex that functions during inflammatory immune responses. The activation of inflammasome will lead to the autoactivation of Capase-1 and subsequent cleavage of proIL-1β and proIL-18，which are key sources of inflammatory manifestations. Recently, the roles of inflammasomes in cancers have been extensively explored, especially in inflammation-induced cancers. In different and specific contexts, inflammasomes exhibit distinct and even contrasting effects in cancer development. In some cases, inflammasomes initiate carcinogenesis through the extrinsic pathway and maintain the malignant cancer microenvironment through the intrinsic pathway. On the contrary, inflammasomes also exert anti-cancer effects by specialized programmed cell death called pyroptosis and immune regulatory functions. The phases and compartments in which inflammasomes are activated strongly influence the final immune effects. We systemically summarize the functions of inflammasomes in inflammation-induced cancers, especially in gastrointestinal and skin cancers. Besides, information about the current therapeutic use of inflammasome-related products and potential future developing directions are also introduced.

Proteins of the IQGAP family display complicated and often contradictory activities in tumorigenesis. IQGAP1 has well documented oncogenic potential and IQGAP2 has putative tumor-suppressive function. IQGAP3 is the latest addition to this family and its role in cancer development remains to be defined. Here we demonstrate IQGAP3 expression is markedly increased in lung cancer tissues at both mRNA and protein levels. Overexpression of IQGAP3 promoted tumor cell growth, and migration and invasion, whereas knockdown of IQGAP3 exhibited opposite effects. Moreover, suppression of IQGAP3 in a lung cancer cell line caused a reduction in the tumorigenicity of these cells in lung tissue after intravenous injection. Furthermore, we showed that IQGAP3 is able to interact with ERK1 and enhance its phosphorylation following treatment with EGF. These data suggest that IQGAP3 may contribute to the pathogenesis of lung cancer by modulating EGFR-ERK signaling.

Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) promotes lung tumorigenesis via attenuating p53 stability Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) promotes lung tumorigenesis via attenuating p53 stability

Ubiquitination and deubiquitination are important post‐translational regulatory mechanisms responsible for fine tuning the antiviral signaling. In this study, we identified a deubiquitinase, the ubiquitin‐specific peptidase 7/herpes virus associated ubiquitin‐specific protease (USP7/HAUSP) as an important negative modulator of virus‐induced signaling. Overexpression of USP7 suppressed Sendai virus and polyinosinic‐polycytidylic acid and poly(deoxyadenylic‐deoxythymidylic)‐induced ISRE and IFN‐β activation, and enhanced virus replication. Knockdown or knockout of endogenous USP7 expression had the opposite effect. Coimmunoprecipitation assays showed that USP7 physically interacted with tripartite motif (TRIM)27. This interaction was enhanced after SeV infection. In addition, TNF receptor‐associated factor family member‐associated NF‐kappa‐B‐binding kinase (TBK)‐1 was pulled down in the TRIM27‐USP7 complex. Overexpression of USP7 promoted the ubiquitination and degradation of TBK1 through promoting the stability of TRIM27. Knockout of endogenous USP7 led to enhanced TRIM27 degradation and reduced TBK1 ubiquitination and degradation, resulting in enhanced type I IFN signaling. Our findings suggest that USP7 acts as a negative regulator in antiviral signaling by stabilizing TRIM27 and promoting the degradation of TBK1.—Cai, J., Chen, H.‐Y., Peng, S.‐J., Meng, J.‐L., Wang, Y., Zhou, Y., Qian, X.‐P., Sun, X.‐Y., Pang, X.‐W., Zhang, Y., Zhang, J. USP7‐TRIM27 axis negatively modulates antiviral type I IFN signaling. FASEB J. 32, 5238–5249 (2018). www.fasebj.org

Reelin promotes the adhesion and drug resistance of multiple myeloma cells via integrin β1 signaling and STAT3