Novel insights into stress-induced susceptibility to influenza: corticosterone impacts interferon-β responses by Mfn2-mediated ubiquitin degradation of MAVS

Abstract

Although stress has been known to increase the susceptibility of pathogen infection, the underlying mechanism remains elusive. In this study, we reported that restraint stress dramatically enhanced the morbidity and mortality of mice infected with the influenza virus (H1N1) and obviously aggravated lung inflammation. Corticosterone (CORT), a main type of glucocorticoids in rodents, was secreted in the plasma of stressed mice. We further found that this stress hormone significantly boosted virus replication by restricting mitochondrial antiviral signaling (MAVS) protein-transduced IFN-β production without affecting its mRNA level, while the deficiency of MAVS abrogated stress/CORT-induced viral susceptibility in mice. Mechanistically, the effect of CORT was mediated by proteasome-dependent degradation of MAVS, thereby resulting in the impediment of MAVS-transduced IFN-β generation in vivo and in vitro. Furthermore, RNA-seq assay results indicated the involvement of Mitofusin 2 (Mfn2) in this process. Gain- and loss-of-function experiments indicated that Mfn2 interacted with MAVS and recruited E3 ligase SYVN1 to promote the polyubiquitination of MAVS. Co-immunoprecipitation experiments clarified an interaction between any two regions of Mfn2 (HR1), MAVS (C-terminal/TM) and SYVN1 (TM). Collectively, our findings define the Mfn2-SYVN1 axis as a new signaling cascade for proteasome-dependent degradation of MAVS and a ‘fine tuning’ of antiviral innate immunity in response to influenza infection under stress.

The disbalance of LRP1 and SIRPα by psychological stress dampens the clearance of tumor cells by macrophages

“…However, mechanistic understanding of the underlying causes is lacking. In this research, we characterized stress hormone GC as the major culprit in stress-promoted cancer susceptibility, similar to our previous discovery regarding stress-induced virus infection 42 . By taking advantage of T lymphocyte-deficient nude mice and macrophage-depleted mice, we further revealed the importance of macrophages in stress-provoked tumorigenesis.…”

Mfn2 is responsible for inhibition of the RIG-I/IRF7 pathway and activation of NLRP3 inflammasome in Seneca Valley virus-infected PK-15 cells to promote viral replication

“…Mfn2 is a master regulator of immune responses during viral infections ( 35 ). Studies have proved that on one hand, Mfn2 inhibited antiviral immune responses by interacting with MAVs or mediating RLR signaling and IRF3 expression during encephalomyocarditis virus (EMCV), Measles, VSV, H1N1 infection ( 36 , 37 ). During infection with human immunodeficiency type 1 (HIV-1) in macrophages, Mfn2 was up-regulated by TREM1.…”

E3 ubiquitin ligase SYVN1 is a key positive regulator for GSDMD-mediated pyroptosis

“…Synoviolin (SYVN1), also known as Hrd1, is one of the RING E3 ligases [ 32 ]. Given that SYVN1 targets numerous substrates such as a proapoptotic factor (IRE1) [ 33 ], B lymphocyte–induced maturation protein 1 (BLIMP1) [ 34 ], and mitochondrial antiviral signaling (MAVS) [ 35 ], it performs distinct functions in different cells. SYVN1 regulates ER-stress-induced cell death by promoting ubiquitination and degradation of IRE1.…”