The ubiquitin E3 ligase TRIM31 promotes aggregation and activation of the signaling adaptor MAVS through Lys63-linked polyubiquitination

Abstract

The signaling adaptor MAVS forms prion-like aggregates to activate an innate antiviral immune response after viral infection. However, the molecular mechanisms that regulate MAVS aggregation are poorly understood. Here we identified TRIM31, an E3 ubiquitin ligase of the TRIM family of proteins, as a regulator of MAVS aggregation. TRIM31 was recruited to mitochondria after viral infection and specifically regulated antiviral signaling mediated by RLR pattern-recognition receptors. TRIM31-deficient mice were more susceptible to infection with RNA virus than were wild-type mice. TRIM31 interacted with MAVS and catalyzed the Lys63 (K63)-linked polyubiquitination of Lys10, Lys311 and Lys461 on MAVS. This modification promoted the formation of prion-like aggregates of MAVS after viral infection. Our findings reveal new insights in the molecular regulation of MAVS aggregation and the cellular antiviral response through TRIM31-mediated K63-linked polyubiquitination of MAVS.

O-GlcNAc Transferase Links Glucose Metabolism to MAVS-Mediated Antiviral Innate Immunity

“…VSV infection caused robust increase in total and K63-linked ubiquitination of MAVS in WT macrophages, as previously described (Liu et al, 2017a; Paz et al, 2009). However, those increases did not occur in Ogt Δmye BMMs, suggesting that OGT was required for MAVS ubiquitination during VSV challenge (Figure 7D).…”

“…In addition, metabolic reprogramming towards increased glucose uptake, glycolysis and PPP has been well defined in innate immune cells that are classically activated by TLR agonists or bacterial infection (Everts et al, 2014; Lachmandas et al, 2016; O’Neill and Pearce, 2016). In contrast, alternative activation of innate immune cells, known as M2 polarization and usually associated with wound healing and tissue repair, generates a metabolic signature that mainly relies on mitochondrial metabolism consuming fatty acid and glutamine (Liu et al, 2017a). Therefore, increased glucose metabolism seems to be a common feature of innate immune responses against PAMPs or DAMPs.…”

“…Previous studies suggest that normal function of MAVS is markedly affected by its ubiquitination (You et al, 2009) and phosphorylation (Liu et al, 2015). We recently identified TRIM31 as a key E3 ubiquitin ligase catalyzing MAVS lysine-63 (K63)-linked ubiquitination, which is required for its antiviral immune function (Liu et al, 2017a). In this study, we characterized OGT-mediated MAVS O -GlcNAcylation on S366, which was induced by RNA virus infection, as a key mechanism for MAVS ubiquitination and activation of antiviral immune responses.…”

Limited and digestive proteolysis: crosstalk between evolutionary conserved pathways

“…Switch between autophagy-and UPSmediated degradation K63 substrate ubiquitination (Zhou et al, 2014;Silva et al, 2015;Liu et al, 2017) ? K48 vs K63 substrate ubiquitination (Park & Cuervo, 2013) It is tempting to speculate that proteophagy may encompass Ub chains linked by K63, as in yeast Ub-proteasomes first aggregate and then embark on proteophagy (Marshall et al, 2016).…”

Ubiquitin-Modifying Enzymes and Regulation of the Inflammasome

“…The DSS colitis data argue that adequate inflammasome activation is required to maintain intestinal epithelial homeostasis. TRIM31 also plays a role in K63-linked polyubiquitination of the signaling adaptor MAVS, promoting aggregation and activation of the downstream antiviral response [78]. Thus, through K63-linked polyubiquitination of MAVS and K48-linked polyubiquitination of NLRP3, TRIM31 is an E3 ligase that plays a role in host defense through multiple innate immune signaling pathways.…”