RNF90 negatively regulates cellular antiviral responses by targeting MITA for degradation.

Bo Yang,Yuhan Cui,Yanzi Liu,Shujun Ma,Ge Zhang,Di Song,Hui Wang,Mengmeng Chen,Fan Chen,Jie Wang,Yue Liu,Fanxiu Zhu

doi:10.1371/journal.ppat.1008387

Abstract

Mediator of IRF3 activation (MITA, also named as STING/ERIS/MPYS/TMEM173), is essential to DNA virus- or cytosolic DNA-triggered innate immune responses. In this study, we demonstrated the negative regulatory role of RING-finger protein (RNF) 90 in innate immune responses targeting MITA. RNF90 promoted K48-linked ubiquitination of MITA and its proteasome-dependent degradation. Overexpression of RNF90 inhibited HSV-1- or cytosolic DNA-induced immune responses whereas RNF90 knockdown had the opposite effects. Moreover, RNF90-deficient bone marrow-derived dendritic cells (BMDCs), bone marrow-derived macrophages (BMMs) and mouse embryonic fibroblasts (MEFs) exhibited increased DNA virus- or cytosolic DNA-triggered signaling and RNF90 deficiency protected mice from DNA virus infection. Taken together, our findings suggested a novel function of RNF90 in innate immunity.

Highlights

The host innate immune system serves as the first line to eliminate viral invasions
We find that RNF90, a known E3 ubiquitin-protein ligase, interacted with Mediator of IRF3 activation (MITA), enhanced the ubiquitination of MITA and promoted the degradation of MITA
Mediator of IRF3 activation (MITA), called stimulator of interferon genes (STING), endoplasmic reticulum interferon stimulator (ERIS), MPYS and Transmembrane protein 173 (TMEM173), plays a very important role in the antiviral signaling pathways, which serves as an adaptor protein for both RNA viruses- and DNA viruses-induced antiviral immune responses [12,13,14,15]

Summary

Introduction

The host innate immune system serves as the first line to eliminate viral invasions. The initiation of antiviral innate immune responses relies on the recognition of pathogen-associated molecular patterns (PAMPs) from invading viruses by a series of pattern recognition receptors (PRRs) [1]. RIG-I-like receptors (RLRs), including retinoic-acid-inducible protein I (RIG-I) and Melanoma differentiation-associated gene 5 (Mda5), serves as intracellular viral RNA receptors [3], whereas cytosolic DNA forms of viruses could be recognized by an array of molecules identified as cytosolic DNA sensors [4], such as DNA-dependent activator of IFN regulatory factors [5], RNA polymerase III [6], IFN-γ-inducible factor 16 [7], DExD/Hbox helicase 41 [8], Ku70 [9], cyclic GMP–AMP (cGAMP) synthase (cGAS) [10], and so on These RNA or DNA receptors recognized the invasion of viruses and triggered the antiviral signaling pathways to produce type I IFN and proinflammatory cytokines, leading to the activation of downstream antiviral innate immune responses to limit the replication of viruses and construct the antiviral microenvironment [11]. MITA-deficient mice showed impaired production of type I IFN in response to DNA virus infection and cytosolic DNA stimulation, susceptible to lethal infection with DNA viruses, including HSV-1, vaccinia virus, and murine gammaherpesvirus 68 (MHV68) [16]

Methods

Results

Discussion

Conclusion