The endoplasmic reticulum-residing chaperone BiP is short-lived and metabolized through N-terminal arginylation
The endoplasmic reticulum-residing chaperone BiP is short-lived and metabolized through N-terminal arginylation
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DOI：
10.1126/scisignal.aan0630
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发表时间：
2018-01-02
影响因子：
7.3
通讯作者：
Kwon, Yong Tae
中科院分区：
文献类型：
--
作者：
Shim, Sang Mi;Choi, Ha Rim;Kwon, Yong Tae
BiP和其他内质网（ER）驻留蛋白被认为是代谢稳定的，主要在ER腔中发挥作用。我们试图评估这些蛋白质的丰度如何动态波动，以应对各种压力，以及它们的亚群如何被重新定位到非ER隔室，如胞质溶胶。我们发现，分子伴侣BiP（也称为GRP 78）是短暂的基础条件下和ER应力。BiP的营业额部分由其氨基末端的N-乙酰基化（Nt-N-乙酰基化）驱动，该N-乙酰基转移酶ATE 1产生N-末端规则途径的自噬N-降解决定子。ER应激引起R-BiP的形成，这种作用在蛋白酶体也被抑制时增加。NT-β-淀粉样磷酸化与BiP在所测试的压力类型下的胞质重定位相关。BiP的胞质重定位不需要未折叠蛋白反应或Sec 61或Derlin 1的功能。一个关键的营业额和NT-β化的BiP的抑制剂是HERP（同型半胱氨酸响应ER蛋白），一个43 kDa的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学抑制也抑制了R-BiP的形成。最后，我们发现，由ER应激和蛋白酶体抑制诱导的胞质R-BiP被路由到自噬空泡和可能的其他代谢命运。这些结果表明，NT-β-淀粉样磷酸化是一种翻译后修饰，调节ER驻留蛋白的功能，定位和代谢命运。
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.