Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) membrane (M) protein is a glycosylated structural protein that localizes to the endoplasmic reticulum (ER) and Golgi and is essential for the assembly of viral particles (Zheng Y et al. 2020; Zhang J. et al. 2020). Ectopic expression of SARS-CoV-2 M protein was found to suppress production of type I and III IFNs in human embryonic kidney 293T cells (HEK293T cells) induced by Sendai virus infection or overexpression of RIG-I (DDX58), MDA5 (IFIH1), MAVS, TBK1 and IKKε (IKBKE) proteins (Zheng Y et al. 2020; Sui L et al. 2021). The inhibitory effect of viral M on the production of type I and III IFNs was also observed in human alveolar basal epithelial (A549) cells (Zheng Y et al. 2020). Co-immunoprecipitation experiments showed interactions between SARS-CoV-2 M and human MAVS, DDX58, IFIH1 and TBK1 in HEK293 cells expressing viral M and RLR signaling molecules (Zheng Y et al. 2020). Binding of viral M to RLR-signaling molecules affected the formation of DDX58:MAVS, MAVS:TBK1, and TRAF3:TBK1 complexes (Zheng Y et al. 2020). The viral M was also found to bind IFIH1, TRAF3, TBK1 and IKBKE, but not DDX58 (Sui L et al. 2021). In addition, the interaction of viral M with TBK1 induced ubiquitin-mediated degradation of TBK1 thus inhibiting IRF3 activation in HEK293T cells (Sui L et al. 2021). Another study reported that SARS-CoV-2 M binds only MAVS, but not DDX58, IFIH1 or TBK1, impairing aggregation of MAVS and recruitment of downstream TRAF3, TBK1 and IRF3 (Fu YZ et al. 2021). Overall, the data suggest that SARS-CoV-2 M protein inhibits MAVS-mediated production of type I and III IFNs by preventing the formation of the MAVS signalosome complex containing DDX58 or IFIH1, MAVS, TRAF3, and TBK1/IKBKE (Zheng Y et al. 2020; Fu YZ et al. 2021; Sui L et al. 2021). However, further studies are needed to clarify the interaction partners of SARS-CoV-2 M downstream of the DDX58/IFIH1:MAVS antiviral signaling axis.

This Reactome event shows binding of the ER-localized SARS-CoV-2 M protein to mitochondrial MAVS assuming that this interaction occurs at the mitochondria-associated ER membranes (MAMs).