Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) M protein is a glycosylated structural protein with three transmembrane (TM) domains. SARS-CoV-2 M predominantly 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). In addition, M associates with the mitochondrion to induce mitophagy (Hui X et al. 2021). Co-immunoprecipitation assay showed that M interacts with microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B or LC3-II) upon co-expression of tagged proteins in human embryonic kidney 293T cells (HEK293T cells). Interaction between Flag-M and endogenous MAP1LC3B was detected in human hepatocellular carcinoma (Huh-7.0) cells. Mutagenesis assay revealed that LC3-interacting region (LIR) of viral M is criitical for this interaction. Further, in M-expressing Huh-7.0 cells, LC3 co-localized with BID, that was used as a marker for mitochondrial organelle. M-expressing Huh-7.0 cells produced higher levels of LC3 in mitochondrial components, but decreased levels of the mitochondrial import receptor subunit TOM20 homolog (TOMM20) and translocase of inner mitochondrial membrane 23 (TIMM23) (Hui X et al. 2021). The SARS-CoV-2 M-mediated mitophagy induction support the findings that expression of M suppressed MAVS- and DDX58-mediated production of type I and III IFNs in human embryonic kidney 293T cells (HEK293T cells) induced by Sendai virus (SeV) infection (Zheng Y et al. 2020; Hui X 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). These data suggest that SARS-CoV-2 infection promotes mitophagy to suppress IFNs production.

This Reactome event shows binding of the ER-localized SARS-CoV-2 M protein to MAP1LC3B (LC3 II) suggesting that this interaction occurs at the mitochondria-associated endoplasmic reticulum membrane (MAM), which was shown to regulate autophagosomes formation (Hamasaki M et al. 2013; reviewed in Yang M et al. 2020).