MLL5 suppresses antiviral innate immune response by facilitating STUB1-mediated RIG-I degradation

Peipei Zhou,Jin Zhong,Lulu Liu,Hui Xiao,Guangxun Meng,Fajian Hou,Xiujie Yuan,Yan Zhang,Lihwen Deng,Xiaodan Ding,Xinhui Hui,Wei Zhang,Xiaoling Wan,Bin Li

doi:10.1038/s41467-018-03563-8

Abstract

Trithorax group protein MLL5 is an important epigenetic modifier that controls cell cycle progression, chromatin architecture maintenance, and hematopoiesis. However, whether MLL5 has a role in innate antiviral immunity is largely unknown. Here we show that MLL5 suppresses the RIG-I-mediated anti-viral immune response. Mll5-deficient mice infected with vesicular stomatitis virus show enhanced anti-viral innate immunity, reduced morbidity, and viral load. Mechanistically, a fraction of MLL5 located in the cytoplasm interacts with both RIG-I and its E3 ubiquitin ligase STUB1, which promotes K48-linked polyubiquitination and proteasomal degradation of RIG-I. MLL5 deficiency attenuates the RIG-I and STUB1 association, reducing K48-linked polyubiquitination and accumulation of RIG-I protein in cells. Upon virus infection, nuclear MLL5 protein translocates from the nucleus to the cytoplasm inducing STUB1-mediated degradation of RIG-I. Our study uncovers a previously unrecognized role for MLL5 in antiviral innate immune responses and suggests a new target for controlling viral infection.

Highlights

Trithorax group protein MLL5 is an important epigenetic modifier that controls cell cycle progression, chromatin architecture maintenance, and hematopoiesis
We found that Mll5−/− bone marrow-derived macrophages (BMDMs) expressed upregulated Ifn-β, Tnf-α, and Il-6 mRNA compared with those from wild-type BMDMs after synthetic RNA duplex poly(I:C) or 5′-pppRNA transfection, but not stimulation with other pathogen-associated molecular pattern (PAMP) ligands, such as lipopolysaccharide (LPS) (TLR4 ligand), CpG-B (TLR9 ligand), R848 (TLR7/ 8 ligand), Pam[3] (TLR1/2 ligand), poly(I:C)(TLR3 ligand), or intracellular IFN stimulatory DNA (ISD) (Fig. 1a)
The levels of Ifn-β and Tnf-α or Il-6 mRNA and the production of IFN-β and tumor necrosis factor (TNF)-α or IL-6 cytokines were significantly higher in Mll5−/− peritoneal macrophages (PMs) (Fig. 1b, c) than in wild-type cells when transfected with poly(I:C) or 5′-pppRNA, but not intracellular ISD

Summary

Introduction

Trithorax group protein MLL5 is an important epigenetic modifier that controls cell cycle progression, chromatin architecture maintenance, and hematopoiesis. Invading pathogens trigger evolutionarily conserved pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), Nod-like receptors (NLRs) and cytosolic sensors of double-stranded DNA These PRRs initiate signaling cascades to induce production of type I interferons (IFNs) and proinflammatory cytokines and invoke the intrinsic antiviral defenses and adaptive immunity to achieve immune clearance[1]. K63-linked polyubiquitination of RIG-I by E3 ligases such as Riplet, tripartite motif-containing protein (Trim) 25, Trim[4], or MEX3C is required for RIG-I activation by altering conformation[3,4,5,6,7] Deubiquitinating enzymes such as CYLD, ubiquitin-specific protease (USP)[3], and USP21 inhibit RIG-I-mediated immune signaling by removing the K63 ubiquitin chain from RIG-I protein[8,9,10]. Whether MLL5 plays a role in innate antiviral immunity is largely unknown

Methods

Results

Conclusion