Research ArticleCELL BIOLOGY

Oncoprotein SND1 hijacks nascent MHC-I heavy chain to ER-associated degradation, leading to impaired CD8+ T cell response in tumor

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Science Advances  29 May 2020:
Vol. 6, no. 22, eaba5412
DOI: 10.1126/sciadv.aba5412

Abstract

SND1 is highly expressed in various cancers. Here, we identify oncoprotein SND1 as a previously unidentified endoplasmic reticulum (ER) membrane–associated protein. The amino-terminal peptide of SND1 predominantly associates with SEC61A, which anchors on ER membrane. The SN domain of SND1 catches and guides the nascent synthesized heavy chain (HC) of MHC-I to ER-associated degradation (ERAD), hindering the normal assembly of MHC-I in the ER lumen. In mice model bearing tumors, especially in transgenic OT-I mice, deletion of SND1 promotes the presentation of MHC-I in both B16F10 and MC38 cells, and the infiltration of CD8+ T cells is notably increased in tumor tissue. It was further confirmed that SND1 impaired tumor antigen presentation to cytotoxic CD8+ T cells both in vivo and in vitro. These findings reveal SND1 as a novel ER-associated protein facilitating immune evasion of tumor cells through redirecting HC to ERAD pathway that consequently interrupts antigen presentation.

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