Molluscum contagiosum virus subverts MHC-I antigen presentation by targeting tapasin for degradation

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Abstract Molluscum contagiosum virus (MCV) is an extremely contagious poxvirus and one of the most common human skin pathogens. It is capable of producing persistent skin lesions that lack an inflammatory response, suggesting potent immune evasion strategies. However, the lack of an animal model or cell line to propagate the virus hampers investigations of the underlying mechanisms of pathogenesis. Here we demonstrate that MCV-encoded MC80 subverts MHC-I antigen presentation to evade CTL recognition. The MC80 ORF is conserved in the genome of all known MCV strains and encodes a type I TM protein with sequence similarity to classical MHC-I proteins. We find that expression of MC80 in human and mouse cells results in retention of host MHC-I in the ER and consequent surface MHC-I downregulation. Mechanistically, we find that MC80 can directly interact with tapasin via its ectodomain and target Tpn for ER-associated degradation in a TM and cytoplasmic tail dependent manner. The degradation of Tpn leads to a loss of TAP and impedes assembly of MHC-I with peptide. Our findings reveal a novel strategy for viral sabotage of the peptide loading complex and provide evidence that MCV actively subverts adaptive immune surveillance.