The ERdj5-Sel1L complex facilitates cholera toxin retrotranslocation.
The ERdj5-Sel1L complex facilitates cholera toxin retrotranslocation.
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ERdj5-Sel1L 复合物促进霍乱毒素逆转位。
DOI：
10.1091/mbc.e12-07-0522
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发表时间：
2013
影响因子：
3.3
通讯作者：
Tsai,Billy
中科院分区：
文献类型：
--
作者：
Williams,JeffreyM;Inoue,Takamasa;Banks,Lindsey;Tsai,Billy
霍乱毒素（CT）从宿主细胞表面运输到内质网（ER），在内质网中，毒素的催化CTA1亚基反转录到细胞质中诱导毒性。在内质网中，E3泛素连接酶Hrd1通过一种未定义的机制捕获CT，为逆转录易位做准备。使用功能丧失和功能获得的方法，我们证明er驻留因子ERdj5部分通过其J结构域促进CTA1逆转录易位。这种Hsp70伴侣调节CTA和ER Hsp70 BiP之间的结合，Hsp70 BiP是一种先前涉及毒素逆转录的伴侣。重要的是，ERdj5直接通过Sel1L的n端管腔结构域与Hrd1适配器Sel1L相互作用，从而将ERdj5与Hrd1复合物连接起来。Sel1L本身也结合CTA并促进毒素反转录。相比之下，两个已建立的Sel1L结合伙伴EDEM1和OS-9在CTA1反转录易位中没有显著作用。因此，我们的研究结果确定了两个内质网因子促进内质网到CTA1的细胞质转运。他们还表明，ERdj5通过与Sel1L结合，在Hrd1复合体附近触发bip -毒素相互作用。我们假设这种情况使hrd1相关的逆转录机制能够在毒素从BiP中释放出来后有效地捕获毒素。
Cholera toxin (CT) traffics from the host cell surface to the endoplasmic reticulum (ER), where the toxin's catalytic CTA1 subunit retrotranslocates to the cytosol to induce toxicity. In the ER, CT is captured by the E3 ubiquitin ligase Hrd1 via an undefined mechanism to prepare for retrotranslocation. Using loss-of-function and gain-of-function approaches, we demonstrate that the ER-resident factor ERdj5 promotes CTA1 retrotranslocation, in part, via its J domain. This Hsp70 cochaperone regulates binding between CTA and the ER Hsp70 BiP, a chaperone previously implicated in toxin retrotranslocation. Importantly, ERdj5 interacts with the Hrd1 adaptor Sel1L directly through Sel1L's N-terminal lumenal domain, thereby linking ERdj5 to the Hrd1 complex. Sel1L itself also binds CTA and facilitates toxin retrotranslocation. By contrast, EDEM1 and OS-9, two established Sel1L binding partners, do not play significant roles in CTA1 retrotranslocation. Our results thus identify two ER factors that promote ER-to-cytosol transport of CTA1. They also indicate that ERdj5, by binding to Sel1L, triggers BiP–toxin interaction proximal to the Hrd1 complex. We postulate this scenario enables the Hrd1-associated retrotranslocation machinery to capture the toxin efficiently once the toxin is released from BiP.