A J-Protein Co-chaperone Recruits BiP to Monomerize IRE1 and Repress the Unfolded Protein Response.
A J-Protein Co-chaperone Recruits BiP to Monomerize IRE1 and Repress the Unfolded Protein Response.
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DOI：
10.1016/j.cell.2017.10.040
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发表时间：
2017-12-14
期刊：
影响因子：
64.5
通讯作者：
Ron D
中科院分区：
文献类型：
--
作者：
Amin-Wetzel N;Saunders RA;Kamphuis MJ;Rato C;Preissler S;Harding HP;Ron D
当未折叠蛋白质在内质网（ER）中积累时，未折叠蛋白反应（UPR）会提高内质网蛋白质折叠能力以恢复蛋白质折叠稳态。未折叠蛋白质通过促进保守的跨膜内质网应激受体IRE1的寡聚化，激活从内质网膜到细胞核的UPR信号传导。然而，内质网应激与IRE1寡聚化及激活之间的关联一直不清楚。在此，我们报道内质网腔辅伴侣蛋白ERdj4/DNAJB9是一种选择性的IRE1抑制因子，它促进内质网腔热休克蛋白70（Hsp70）BiP与IRE1α的内质网腔应激感应结构域（IRE1LD）之间形成复合物。在体外，BiP和IRE1LD之间形成复合物需要ERdj4。ERdj4与IRE1LD结合，并通过刺激ATP水解招募BiP，强行破坏IRE1二聚体。未折叠蛋白质竞争BiP并使IRE1LD恢复到其默认的二聚体和活性状态。这些观察结果确立了BiP及其J结构域辅伴侣蛋白是UPR的关键调节因子。
内质网辅伴侣蛋白ERdj4选择性抑制IRE1信号传导
ERdj4与IRE1内质网腔结构域结合并招募Hsp70 BiP
招募的BiP水解ATP以破坏活性IRE1内质网腔结构域二聚体
未折叠蛋白质竞争抑制机制以恢复IRE1二聚体
伴侣蛋白和错误折叠蛋白质对未折叠蛋白反应的调控的分子基础
When unfolded proteins accumulate in the endoplasmic reticulum (ER), the unfolded protein response (UPR) increases ER-protein-folding capacity to restore protein-folding homeostasis. Unfolded proteins activate UPR signaling across the ER membrane to the nucleus by promoting oligomerization of IRE1, a conserved transmembrane ER stress receptor. However, the coupling of ER stress to IRE1 oligomerization and activation has remained obscure. Here, we report that the ER luminal co-chaperone ERdj4/DNAJB9 is a selective IRE1 repressor that promotes a complex between the luminal Hsp70 BiP and the luminal stress-sensing domain of IRE1α (IRE1LD). In vitro, ERdj4 is required for complex formation between BiP and IRE1LD. ERdj4 associates with IRE1LD and recruits BiP through the stimulation of ATP hydrolysis, forcibly disrupting IRE1 dimers. Unfolded proteins compete for BiP and restore IRE1LD to its default, dimeric, and active state. These observations establish BiP and its J domain co-chaperones as key regulators of the UPR. The endoplasmic reticulum co-chaperone ERdj4 selectively represses IRE1 signaling ERdj4 associates with the IRE1 luminal domain and recruits the Hsp70 BiP Recruited BiP hydrolyzes ATP to disrupt the active IRE1 luminal domain dimer Unfolded proteins compete for the repressive machinery to restore IRE1 dimers Molecular basis for the regulation of the unfolded protein response by chaperones and misfolded proteins.
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影响因子：
64.8
作者：
Kim, Min-Sik;Pinto, Sneha M.;Getnet, Derese;Nirujogi, Raja Sekhar;Manda, Srikanth S.;Chaerkady, Raghothama;Madugundu, Anil K.;Kelkar, Dhanashree S.;Isserlin, Ruth;Jain, Shobhit;Thomas, Joji K.;Muthusamy, Babylakshmi;Leal-Rojas, Pamela;Kumar, Praveen;Sahasrabuddhe, Nandini A.;Balakrishnan, Lavanya;Advani, Jayshree;George, Bijesh;Renuse, Santosh;Selvan, Lakshmi Dhevi N.;Patil, Arun H.;Nanjappa, Vishalakshi;Radhakrishnan, Aneesha;Prasad, Samarjeet;Subbannayya, Tejaswini;Raju, Rajesh;Kumar, Manish;Sreenivasamurthy, Sreelakshmi K.;Marimuthu, Arivusudar;Sathe, Gajanan J.;Chavan, Sandip;Datta, Keshava K.;Subbannayya, Yashwanth;Sahu, Apeksha;Yelamanchi, Soujanya D.;Jayaram, Savita;Rajagopalan, Pavithra;Sharma, Jyoti;Murthy, Krishna R.;Syed, Nazia;Goel, Renu;Khan, Aafaque A.;Ahmad, Sartaj;Dey, Gourav;Mudgal, Keshav;Chatterjee, Aditi;Huang, Tai-Chung;Zhong, Jun;Wu, Xinyan;Shaw, Patrick G.;Freed, Donald;Zahari, Muhammad S.;Mukherjee, Kanchan K.;Shankar, Subramanian;Mahadevan, Anita;Lam, Henry;Mitchell, Christopher J.;Shankar, Susarla Krishna;Satishchandra, Parthasarathy;Schroeder, John T.;Sirdeshmukh, Ravi;Maitra, Anirban;Leach, Steven D.;Drake, Charles G.;Halushka, Marc K.;Prasad, T. S. Keshava;Hruban, Ralph H.;Kerr, Candace L.;Bader, Gary D.;Iacobuzio-Donahue, Christine A.;Gowda, Harsha;Pandey, Akhilesh
通讯作者：
Pandey, Akhilesh
影响因子：
7.7
作者：
De Los Rios P;Barducci A
通讯作者：
Barducci A
影响因子：
7.7
作者：
Carrara M;Prischi F;Nowak PR;Kopp MC;Ali MM
通讯作者：
Ali MM
DOI：
10.15252/embj.201489183
发表时间：
2015-06-03
期刊：
The EMBO journal
影响因子：
--
作者：
Carrara M;Prischi F;Nowak PR;Ali MM
通讯作者：
Ali MM
影响因子：
64.5
作者：
Lee, Kenneth P. K.;Dey, Madhusudan;Sicheri, Frank
通讯作者：
Sicheri, Frank