Oncoprotein SND1 hijacks nascent MHC-I heavy chain to ER-associated degradation, leading to impaired CD8(+) T cell response in tumor
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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癌蛋白 SND1 劫持新生 MHC-I 重链以进行 ER 相关降解，导致肿瘤中 CD8( ) T 细胞反应受损
DOI：
10.1126/sciadv.aba5412
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发表时间：
2020
期刊：
影响因子：
13.6
通讯作者：
Yang Jie
中科院分区：
文献类型：
--
作者：
Wang Yuan;Wang Xinting;Cui Xiaoteng;Zhuo Yue;Li Hongshuai;Ha Chuanbo;Xin Lingbiao;Ren Yuanyuan;Zhang Wei;Sun Xiaoming;Ge Lin;Liu Xin;He Jinyan;Zhang Tao;Zhang Kai;Yao Zhi;Yang Xi;Yang Jie
SND 1在多种癌症中高度表达。在这里，我们确定癌蛋白SND 1作为一个以前未确定的内质网（ER）膜相关蛋白。SND 1的氨基端肽主要与SEC 61 A结合，SEC 61 A锚定在ER膜上。SND 1的SN结构域捕获并引导MHC-I的新生合成重链（HC）至ER相关降解（ERAD），阻碍MHC-I在ER腔中的正常组装。在荷瘤小鼠模型中，特别是在转基因OT-I小鼠中，SND 1的缺失促进了B16 F10和MC 38细胞中MHC-I的呈递，并且CD 8 +T细胞在肿瘤组织中的浸润显著增加。进一步证实，SND 1在体内和体外均损害肿瘤抗原向细胞毒性CD 8 +T细胞的呈递。这些发现揭示了SND 1作为一种新的ER相关蛋白，通过将HC重定向至ERAD途径从而中断抗原呈递来促进肿瘤细胞的免疫逃避。
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.