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The endoplasmic reticulum–residing chaperone BiP is short-lived and metabolized through N-terminal arginylation
Science Signaling ( IF 6.7 ) Pub Date : 2018-01-02 , DOI: 10.1126/scisignal.aan0630
Sang Mi Shim 1, 2 , Ha Rim Choi 1, 2 , Ki Woon Sung 1, 2 , Yoon Jee Lee 1, 2 , Sung Tae Kim 1, 2, 3 , Daeho Kim 1, 4 , Su Ran Mun 1, 2 , Joonsung Hwang 5 , Hyunjoo Cha-Molstad 5 , Aaron Ciechanover 1, 6 , Bo Yeon Kim 5 , Yong Tae Kwon 1, 2, 7
Affiliation  

BiP and other endoplasmic reticulum (ER)–resident proteins are thought to be metabolically stable and to function primarily in the ER lumen. We sought to assess how the abundance of these proteins dynamically fluctuates in response to various stresses and how their subpopulations are relocated to non-ER compartments such as the cytosol. We showed that the molecular chaperone BiP (also known as GRP78) was short-lived under basal conditions and ER stress. The turnover of BiP was in part driven by its amino-terminal arginylation (Nt-arginylation) by the arginyltransferase ATE1, which generated an autophagic N-degron of the N-end rule pathway. ER stress elicited the formation of R-BiP, an effect that was increased when the proteasome was also inhibited. Nt-arginylation correlated with the cytosolic relocalization of BiP under the types of stress tested. The cytosolic relocalization of BiP did not require the functionality of the unfolded protein response or the Sec61- or Derlin1-containing translocon. A key inhibitor of the turnover and Nt-arginylation of BiP was HERP (homocysteine-responsive ER protein), a 43-kDa ER membrane–integrated protein that is an essential component of ER-associated protein degradation. Pharmacological inhibition of the ER-Golgi secretory pathway also suppressed R-BiP formation. Finally, we showed that cytosolic R-BiP induced by ER stress and proteasomal inhibition was routed to autophagic vacuoles and possibly additional metabolic fates. These results suggest that Nt-arginylation is a posttranslational modification that modulates the function, localization, and metabolic fate of ER-resident proteins.



中文翻译:

内质网陪伴分子BiP寿命短,并通过N末端精氨酰化代谢

BiP和其他内质网(ER)驻留蛋白被认为是代谢稳定的,并且主要在ER内腔中起作用。我们试图评估这些蛋白质的丰度如何响应各种压力而动态波动,以及它们的亚群如何重定位到非ER区域(如细胞质)。我们表明,分子伴侣BiP(也称为GRP78)在基础条件和内质网应激下是短暂的。BiP的营业额部分受精氨酸转移酶ATE1的氨基末端精氨化作用(Nt-精氨化)的驱动,后者产生了N端规则途径的自噬N-德格隆。内质网应激引起R-BiP的形成,当蛋白酶体也被抑制时,这种作用会增强。在测试的压力类型下,Nt-精氨酰化与BiP的胞质再定位相关。BiP的胞质重定位不需要展开的蛋白应答或包含Sec61或Derlin1的转位子的功能。BiP转换和Nt-精氨酰化的关键抑制剂是HERP(高半胱氨酸反应性ER蛋白),它是一种43 kDa ER膜整合蛋白,是ER相关蛋白降解的重要组成部分。ER-高尔基体分泌途径的药理抑制作用也抑制了R-BiP的形成。最后,我们表明,由内质网应激和蛋白酶体抑制诱导的胞质R-BiP被路由至自噬泡和可能的其他代谢命运。这些结果表明,Nt-精氨酰化是翻译后修饰,可调节功能,定位,

更新日期:2018-01-03
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