Ubiquitin-Conjugating Enzyme 2S Enhances Viral Replication by Inhibiting Type I IFN Production through Recruiting USP15 to Deubiquitinate TBK1

Li Huang,Hongyang Liu,Kunli Zhang,Qingwen Meng,Liang Hu,Yuanfeng Zhang,Zhida Xiang,Jiangnan Li,Yuying Yang,Yali Chen,Shangjin Cui,Hong Tang,Huadong Pei,Zhigao Bu,Changjiang Weng

doi:10.1016/j.celrep.2020.108044

Abstract

Type I interferon (IFN) plays an essential role in the host innate immune responses. Several ubiquitin-conjugating enzyme (E2) family members were reported to regulate type I IFN production and host antiviral immune responses. However, the molecular mechanisms are still not fully understood. Here, we report that UBE2S acts as a negative regulator in the type I IFN signaling pathway. Ectopic expression of UBE2S inhibits host antiviral immune responses and enhances viral replications, whereas deficiency of UBE2S enhances host antiviral immune responses and suppresses viral replications both invitro and invivo. Inhibition of type І IFN production by UBE2S is independent on its E2 and E3 enzymic activity. Mechanistically, UBE2S interacts with TBK1 and recruits ubiquitin-specific protease 15 (USP15) to remove Lys63 (K63)-linked polyubiquitin chains of TBK1. Our findings reveal a role of the UBE2S-USP15-TBK1 axis in the regulation of host antiviral innate immune responses.

Highlights

The production of type I interferon (IFN) is a fundamental innate cellular response in the defense against invading pathogens (Stetson and Medzhitov, 2006)
To investigate which member of E2s is associated with type I IFN signaling, we performed an unbiased screening of the role of E2s in type I IFN production and found that ubiquitin-conjugating enzyme E2S (UBE2S) and several other E2s have the inhibitory effect on Ifnb1 mRNA levels after vesicular stomatitis virus (VSV) or herpes simplex virus 1 (HSV-1) infection (Figures S1A and S1B), whereas a few members, including UBE2D3 and UBE2N, increased Ifnb1 mRNA levels following VSV and HSV-1 infections
We found that ectopically expressed UBE2S significantly decreased the mRNA levels of Ifnb1 induced by Sendai virus (SeV), VSV, encephalomyocarditis virus (EMCV), and HSV-1 infections (Figures 1A–1D) and inhibited the phosphorylation of IFN regulatory factor 3 (IRF3) induced by VSV and HSV-1 infections (Figures 1E and 1F)

Summary

Introduction

The production of type I interferon (IFN) is a fundamental innate cellular response in the defense against invading pathogens (Stetson and Medzhitov, 2006). When microbes infect the host, pathogen-associated molecular patterns (PAMPs), including viral DNA, viral RNA, and surface glycoproteins, are recognized by pattern-recognition receptors (PRRs) expressed in multiple immune cells (Kawai and Akira, 2010). Upon the recognition of PAMPs, these PRRs recruit different adaptors, such as TLR/interleukin 1R (IL-1R) domain-containing adaptor-protein-inducing IFN-b (TRIF) (Sato et al, 2003), mitochondrial antiviral signaling protein (MAVS) (Seth et al, 2005), or stimulator of IFN gene (STING) (Ishikawa and Barber, 2008), to activate TANK-binding kinase 1 (TBK1). Secreted type I IFNs bind to the IFNa/b receptor (IFNAR) to activate the JAK/STAT signaling pathway, triggering the expression of antiviral genes, including IFN-stimulated genes (ISGs) (Platanias, 2005)

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Conclusion