Golgi versus endocytic trafficking in the delivery of major histocompatibility complex II molecules to antigen-loading compartments

Antigen presentation on MHC II is crucial for generating immune responses against pathogens. Unfortunately, many pathogens-including SARS-CoV-2-can suppress immune responses by impairing this process. While the mechanisms for this immune evasion is known for some pathogens, it remains unclear how SARS-CoV-2 limits antigen presentation. During antigen presentation MHC II is loaded with pathogen-derived peptides inside of a lysosome-derived MHC II-loading compartment (MIIC). However, how MHC II is delivered here is controversial, but occurs either via export to the cell surface followed by reinternalization and trafficking to the MIIC, or direct Golgi-to-MIIC transport. We previously identified Erc1 and Rab6-regulators of Golgi-to-lysosome transport-on MIICs. We also demonstrated that Erc1 accumulates on the MIIC and is required for MHC II delivery, supporting the direct trafficking route. Additionally, several components of this trafficking pathway, including Erc1, have been identified as SARS-CoV-2 interacting proteins, suggesting that antigen presentation is manipulated via the direct route. Thus, we hypothesize that Erc1 mediates the direct Golgi-to-MIIC transport of MHC II, and that SARS-CoV-2 targets Erc1 to block this route. Time-lapse microscopy will be used to determine the definitive MHC transport route, and knockdowns of trafficking regulators will be performed to elucidate their role in MHC II delivery. Host proteins found to interact with SARS-CoV-2 proteins through immunoprecipitation and mass spectrophotometry will also be knocked down to determine whether these interactions are necessary for immune evasion. Understanding the mechanisms by which SARS-CoV-2 inhibits antigen presentation will be essential for developing vaccines and therapeutics for COVID-19.