RNF115 plays dual roles in innate antiviral responses by catalyzing distinct ubiquitination of MAVS and MITA

Abstract

MAVS and MITA are essential adaptor proteins mediating innate antiviral immune responses against RNA and DNA viruses, respectively. Here we show that RNF115 plays dual roles in response to RNA or DNA virus infections by catalyzing distinct types of ubiquitination of MAVS and MITA at different phases of viral infection. RNF115 constitutively interacts with and induces K48-linked ubiquitination and proteasomal degradation of homeostatic MAVS in uninfected cells, whereas associates with and catalyzes K63-linked ubiquitination of MITA after HSV-1 infection. Consistently, the protein levels of MAVS are substantially increased in Rnf115−/− organs or cells without viral infection, and HSV-1-induced aggregation of MITA is impaired in Rnf115−/− cells compared to the wild-type counterparts. Consequently, the Rnf115−/− mice exhibit hypo- and hyper-sensitivity to EMCV and HSV-1 infection, respectively. These findings highlight dual regulation of cellular antiviral responses by RNF115-mediated ubiquitination of MAVS and MITA and contribute to our understanding of innate immune signaling.

The E3 ubiquitin ligase RNF115 regulates phagosome maturation and host response to bacterial infection

“…trafficking proteins. Similar to Zhang et al, who showed that loss of RNF115 affected immune responses to HSV-1(Zhang et al, 2020), innate immune responses were affected in our experiments. However, in our model, only for signalling from pathogens within the phagosome.…”

“…As RNF115 was previously reported to bind to Rab7, and play a role in receptor trafficking and anti-viral host response by interfering with endo-lysosomal pathways (Li et al, 2020, Miyakawa et al, 2009, Nityanandam & Serra-Moreno, 2014, Zhang et al, 2020), we tested if RNF115 regulated phagosomal functions.…”

Identification and validation of circulating miRNAs as potential new biomarkers for severe liver disease in patients with leptospirosis

“…Regarding Ras signalling pathway, while currently highlighting within the field of cancer biology, this superfamily of small GTPases also plays fundamental roles in immunity and inflammation [ 32 ]. Moreover, the expression of main potential innate immunity and inflammation signaling molecules such as RNF11, UBE2N and RNF115 [ 33 – 35 ] were found to have high degree of interaction in the PPI network.…”

cGAS‐STING pathway: post‐translational modifications and functions in sterile inflammatory diseases

“…TRIM56 and TRIM32 promotes the recruitment of TBK1 through conjugation of K63-linked poly-ubiquitination of STING (TRIM56 at position K150, and TRIM32 at K20, K224, and K236), which positively regulate STING-dependent signal activation [109,110]. Similarly, mitochondrial E3 ubiquitin protein ligase 1 (MUL1) and RNF115 directly interact with STING and catalyze K63-linked polyubiquitination of STING at K224 and K20, K224, K289, respectively, to promote its translocation from ER to Golgi apparatus for activations [111,112]. Conversely, cytosolic DNA stimulation induces the expression of myb-like, SWIRM, and MPN domains 1 protein (MYSM1), which interacts with STING and cleaves STING K63-linked ubiquitination at K150 to restrict STING overactivation [113].…”