Mitochondrially localised MUL1 is a novel modulator of antiviral signaling

Abstract

The innate immune response to virus must be balanced to eliminate infection yet limit damaging inflammation. A critical arm of the antiviral response is launched by the retinoic acid-inducible-gene I (RIG-I) protein. RIG-I is activated by viral RNA then associates with the mitochondrial antiviral signaling (MAVS) protein to subsequently induce potent inflammatory cytokines. Here, we demonstrate the mitochondrial E3 ubiquitin protein ligase 1 (MUL1) is a crucial moderator of RIG-I signaling. MUL1 is localized to the mitochondria where it interacts with MAVS and catalyzes RIG-I post-translational modifications that inhibit RIG-I-dependent cell signaling. Accordingly, depletion of MUL1 potentiated RIG-I mediated nuclear factor-kappa B (NF-κB) and interferon (IFN) β reporter activity. Moreover, depletion of MUL1 boosted the antiviral response and increased proinflammatory cytokines following challenge with the RNA mimetic poly I:C and Sendai virus. We therefore submit that MUL1 is a novel regulator of the RIG-I-like receptor-dependent antiviral response, that otherwise functions to limit inflammation.

Keeping the immune system in check: a role for mitophagy

“…Interestingly, three ubiquitin ligases, Smurf1, Mul1 and Gp78 that have been implicated in regulation of mitophagy, are also linked to negative regulation of MAVS signaling. The ubiquitin ligase Smurf1 mediates the degradation of MAVS, 87 and Mul1 modulates MAVS signaling by inhibitory posttranslational modification of RIG‐I 88 . Furthermore, Gp78 was shown to regulate MAVS using both ubiquitin‐dependent and ‐independent mechanisms 89 .…”

Mitochondria: sensors and mediators of innate immune receptor signaling

“…Interestingly, MFN2 can also act as an inhibitor of antiviral signaling, a function that may be distinct from its role in mitochondrial dynamics [4]. Recently, another mitochondrial fusion/fission protein, mitochondrial E3 ubiquitin protein ligase 1 (MUL1), has been shown to directly interact with MAVS and modulate RLR responses [9] (Fig.2). Taken together, these data demonstrate that impaired fission or fusion leading to mitochondrial fragmentation dampens RLR signaling.…”

The Arabidopsis E3 Ubiquitin Ligase SP1 Targets to Chloroplasts, Peroxisomes, and Mitochondria

“…It is not uncommon for an E3 ubiquitin ligase to be multifunctional and have different substrates. For example, MAPL itself has several known substrate proteins in different physiological processes, including the mitochondrial and peroxisomal fission factor dynaminrelated protein DRP1 (Braschi et al, 2009), E3 ubiquitin ligase TRAF2 in mitochondrial hyperfusion (Zemirli et al, 2014), ULK1 in mitophagy (Li et al, 2015), mitofusin in mitochondrial integrity maintenance (Yun et al, 2014), RIG-I in mitochondrial antiviral response (Jenkins et al, 2013), the Ser/Thr kinase Akt in cell proliferation and viability (Bae et al, 2012), and p53 and p73 when they translocate to mitochondria under cell stress (Jung et al, 2011;Min et al, 2015). When we performed a phylogenetic analysis using SP1, its two homologs from Arabidopsis SPL1 and SPL2, and homologous sequences from other eukaryotic species, MAPL was grouped together with SP1 and SPL1 in the same subclade conserved in plants and animals, whereas SPL2 belonged to a plant-specific subclade, suggesting a strong evolutionary relationship between SP1 and MAPL (Pan et al, 2016).…”