Serine Residues in the Cytosolic Tail of the T-cell Antigen Receptor α-Chain Mediate Ubiquitination and Endoplasmic Reticulum-associated Degradation of the Unassembled Protein
Serine Residues in the Cytosolic Tail of the T-cell Antigen Receptor α-Chain Mediate Ubiquitination and Endoplasmic Reticulum-associated Degradation of the Unassembled Protein
复制标题
DOI：
10.1074/jbc.m110.127936
复制
发表时间：
2010-07-30
影响因子：
4.8
通讯作者：
Bonifacino, Juan S.
中科院分区：
文献类型：
--
作者：
Ishikura, Shuhei;Weissman, Allan M.;Bonifacino, Juan S.
T细胞抗原受体(TCR)α链(TCRα)是一种I型完整的膜蛋白，当它不能组装成异构体TCR复合体时，它会变得泛素化，并靶向内质网(ER)相关降解(ERAD)途径。值得注意的是，TCRα的胞浆尾部只有5个氨基酸残基(即RLWSS)，其中没有一个是传统的泛素受体赖氨酸。在此，我们报告了TCRα胞浆尾部的两个保守的丝氨酸残基被替换为丙氨酸降低了泛素化，而额外的丝氨酸残基的放置则增强了泛素化。此外，胞质丝氨酸残基被其他泛素化残基(即半胱氨酸、苏氨酸或赖氨酸)取代，使得泛素化得以发生。丝氨酸依赖的泛素化与ERAD的TCRα靶向完全相关。我们还发现，这种泛素化是由内质网定位的泛素连接酶Hrd1介导的。这些发现表明，丝氨酸依赖的、Hrd1介导的泛素化将TCRα靶向ERAD途径。
The T-cell antigen receptor (TCR) alpha-chain (TCR alpha) is a type I integral membrane protein that becomes ubiquitinated and targeted to the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway when it fails to assemble into the heteromeric TCR complex. Remarkably, TCR alpha has a cytosolic tail of only five amino acid residues (i.e. RLWSS), none of which is the conventional ubiquitin acceptor, lysine. Herein we report that substitution of two conserved serine residues in the cytosolic tail of TCR alpha to alanine decreased ubiquitination, whereas placement of additional serine residues enhanced it. Moreover, replacement of the cytosolic serine residues by other ubiquitinatable residues (i.e. cysteine, threonine, or lysine) allowed ubiquitination to take place. Serine-dependent ubiquitination perfectly correlated with targeting of TCR alpha for ERAD. We also found that this ubiquitination was mediated by the ER-localized ubiquitin ligase, HRD1. These findings indicate that serine-dependent, HRD1-mediated ubiquitination targets TCR alpha to the ERAD pathway.