Negative Regulation of RNF90 on RNA Virus-Triggered Antiviral Immune Responses Targeting MAVS.

Jie Wang,Hui Wang,Yuhan Cui,Xiaowen Ren,Xiao Qin,Bo Yang,Ge Zhang,Di Song,Jingliang Sun,Shujun Ma,Yulu Huang,Yanzi Liu,Yue Liu

doi:10.3389/fimmu.2021.730483

Jie Wang, Hui Wang + Show 11 more

Open Access

https://doi.org/10.3389/fimmu.2021.730483

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Abstract

The antiviral innate immunity is the first line of host defense against viral infection. Mitochondrial antiviral signaling protein (MAVS, also named Cardif/IPS-1/VISA) is a critical protein in RNA virus-induced antiviral signaling pathways. Our previous research suggested that E3 ubiquitin-protein ligases RING-finger protein (RNF90) negatively regulate cellular antiviral responses by targeting STING for degradation, though its role in RNA virus infection remains unknown. This study demonstrated that RNF90 negatively regulated RNA virus-triggered antiviral innate immune responses in RNF90-silenced PMA-THP1 cells, RNF90-deficient cells (including HaCaTs, MEFs, and BMDMs), and RNF90-deficient mice. However, RNF90 regulated RNA virus-triggered antiviral innate immune responses independent of STING. RNF90 promoted K48-linked ubiquitination of MAVS and its proteasome-dependent degradation, leading to the inhibition of innate immune responses. Altogether, our findings suggested a novel function and mechanism of RNF90 in antiviral innate immunity.

Highlights

RNA viruses, which have RNA as their genetic material, including single-stranded RNA viruses and double-stranded RNA viruses, cause many kinds of human infectious diseases [1, 2]
PMATHP1 cells were transfected with control small interfering RNA (siRNA) (SC) or two pairs of siRNA oligonucleotides specific for RNF90 RNA (R2, R3)
The results indicated RNF90 knockdown decreased vesicular stomatitis virus (VSV) titers (Figure 2E), suggesting the VSV-triggered antiviral immune responses was inhibited by RNF90

Summary

Introduction

RNA viruses, which have RNA as their genetic material, including single-stranded RNA (ssRNA) viruses and double-stranded RNA (dsRNA) viruses, cause many kinds of human infectious diseases [1, 2]. A lot of RNA viruses, such as human immunodeficiency virus (HIV), hepatitis C virus (HCV), Ebola virus, Zika virus, respiratory syncytial virus (RSV), influenza viruses, yellow fever virus, dengue virus, severe acute respiratory syndrome (SARS)-associated coronavirus (SARS-CoV), and SARS-CoV-2 are well-known viruses that are infectious and cause serious, even deadly, syndromes in humans [3, 4]. The host antiviral immune responses are initiated by the sensing of pathogen-associated molecular patterns (PAMPs) from invading viruses by a series of pattern recognition receptors (PRRs), which results in the production of type I interferons (IFNs) and other cytokines or chemokines essential to host antiviral responses [6]. For RNA viruses, the viral nucleic acids are critical PAMPs, and the viral RNAs are recognized by TLR3 or RIG-I-like receptors (RLRs) [7].

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