The SARS-CoV-2 M protein broadly inhibits host protein trafficking and secretion through the host cell secretory pathway

Coronavirus (CoV) spillover events have caused three recent outbreaks, including the COVID-19 pandemic. In addition to these highly pathogenic CoVs, there are four seasonal ‘common cold’ CoVs that circulate in humans. It is not well understood how differences between CoVs contribute to pathogenesis and the complexities of what made SARS-CoV-2 a highly transmissible and pathogenic virus compared to previously identified CoVs. Non-structural and accessory proteins of CoVs have been investigated for disruption of host-cell signalling pathways, while CoV structural proteins such as Membrane (M) have been overlooked for similar host interactions. M is the most abundant viral glycoprotein in the virus envelope, and it coordinates the other CoV structural proteins at the ER-Golgi intermediate compartment (ERGIC) for assembly. The ERGIC is an organelle that facilitates bidirectional transport of cargo between the ER and Golgi, and it is rarely repurposed as a site of virus assembly; only CoVs and arenaviruses assemble at the ERGIC. The ERGIC serves as a critical player in secretion and trafficking of host proteins through the secretory pathway. We have discovered three host response pathways that are inhibited by SARS-CoV-2 M, all of which traffic through the secretory pathway. These host proteins are STING (IFN response), ATF6 (ER unfolded protein response) and SREBP2 (cholesterol biosynthesis). Our current objectives aim to determine how M inhibits the secretory pathway and characterize the consequences of interference with these secretory pathway-dependent signaling pathways for both the host cell and SARS-CoV-2. Findings from this research have the potential to identify new roles for the SARS-CoV-2 M protein in repurposing the host secretory pathway and interfering with a variety of host cell processes, revealing how these processes could be exploited to elicit antiviral effects during SARS-CoV-2 replication.