MicroRNA-200c-targeted contactin 1 facilitates the replication of influenza A virus by accelerating the degradation of MAVS.

Influenza A viruses (IAVs) continuously challenge the poultry industry and human health. Elucidation of the host factors that modulate the IAV lifecycle is vital for developing antiviral drugs and vaccines. In this study, we infected A549 cells with IAVs and found that host protein contactin-1 (CNTN1), a member of the immunoglobulin superfamily, enhanced viral replication. Bioinformatic prediction and experimental validation indicated that the expression of CNTN1 was reduced by microRNA-200c (miR-200c) through directly targeting. We further showed that CNTN1-modulated viral replication in A549 cells is dependent on type I interferon signaling. Co-immunoprecipitation experiments revealed that CNTN1 specifically interacts with MAVS and promotes its proteasomal degradation by removing its K63-linked ubiquitination. Moreover, we discovered that the deubiquitinase USP25 is recruited by CNTN1 to catalyze the deubiquitination of K63-linked MAVS. Consequently, the CNTN1-induced degradation cascade of MAVS blocked RIG-I-MAVS-mediated interferon signaling, leading to enhanced viral replication. Taken together, our data reveal novel roles of CNTN1 in the type I interferon pathway and regulatory mechanism of IAV replication.

The PB1 protein of influenza A virus inhibits the innate immune response by targeting MAVS for NBR1-mediated selective autophagic degradation.

Influenza A virus (IAV) has evolved various strategies to counteract the innate immune response using different viral proteins. However, the mechanism is not fully elucidated. In this study, we identified the PB1 protein of H7N9 virus as a new negative regulator of virus- or poly(I:C)-stimulated IFN induction and specifically interacted with and destabilized MAVS. A subsequent study revealed that PB1 promoted E3 ligase RNF5 to catalyze K27-linked polyubiquitination of MAVS at Lys362 and Lys461. Moreover, we found that PB1 preferentially associated with a selective autophagic receptor neighbor of BRCA1 (NBR1) that recognizes ubiquitinated MAVS and delivers it to autophagosomes for degradation. The degradation cascade mediated by PB1 facilitates H7N9 virus infection by blocking the RIG-I-MAVS-mediated innate signaling pathway. Taken together, these data uncover a negative regulatory mechanism involving the PB1-RNF5-MAVS-NBR1 axis and provide insights into an evasion strategy employed by influenza virus that involves selective autophagy and innate signaling pathways.

Influenza D virus Matrix protein 1 restricts the type I interferon response by degrading TRAF6.

Influenza D virus (IDV) is an emerged virus that was first isolated in 2011 in the United States. Evidence suggests that IDV has broad host tropism and zoonotic potential. However, the immune evasion mechanism of IDV has not been explored. In the present study, we identified that the Matrix protein 1 (M1) of IDV is a negative regulator of virus- or RIG-IN-triggered type I interferon induction. Co-immunoprecipitation experiments revealed that M1 specifically interacts with tumor necrosis factor receptor associated factor 6 (TRAF6) and potentiates its proteasomal degradation by promoting K48-linked polyubiquitination. Moreover, we discovered that E3 ubiquitin ligase KEAP1 is recruited by M1 to catalyze K48-linked polyubiquitination of TRAF6, and promotes TRAF6 destabilization. Consequently, the degradation cascade mediated by M1 blocks RIG-I-TRAF6 mediated interferon signaling. Taken together, our findings reveal a negative regulatory role for the IDV M1 in the type І interferon pathway.

[Clinical observation of the curative effect of Qiangxin Mixture on congestive heart failure].

OBJECTIVE: To investigate the efficacy of Qiangxin Mixture in patients with congestive heart failure (CHF). METHODS: Sixty cases of CHF were randomly divided into Qiangxin Mixture group (treatment group, n=30) and digoxin group (control group, n=30). The total clinical effective rate, integra of the symptoms of kidney deficiency, classification of functional capacity of the New York Heart Association (NYHA), and echocardiogram [ejection fraction (EF), cardiac output (CO), interventricular septal thickness (IVST), posterior wall thickness (PWT), left ventricular mass index (LVMI)] as well as the measurement of plasma endothelin, angiotensin II and atrial natriuretic peptide were observed in both groups. RESULTS: The total clinical effective rate of Qiangxin Mixture group was 87%, and improvement was significantly observed in the Lee CHF score, classification of functional capacity of the NYHA, EF and CO (P<0.05, vs before treatment), but no significant improvement in digoxin group (P>0.05). The integra of the symptoms of kidney deficiency, the levels of plasma ET, Ang II and ANP decreased significantly (P<0.01, vs before treatment and digoxin group respectively). IVST, PWT and LVMI were also reduced significantly (P<0.01, vs before treatment; P<0.05 vs digoxin group). CONCLUSION: The Qiangxin Mixture is effective in enhancing cardiac contraction, improving hemodynamics in the short-term and rectifying some indexes in the long-term, so it could postpone the processes of CHF. This mechanism may be related to decreasing the stimulating factors (angiotensin, endothelin) which trigger the cardiac remodeling, delaying or reversing the cardiac remodeling.