当前位置: X-MOL 学术Mol. Biol. Cell › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
DNAJB12 and Hsp70 Triage Arrested Intermediates of N1303K-CFTR for ER Associated-Autophagy
Molecular Biology of the Cell ( IF 3.3 ) Pub Date : 2021-02-03 , DOI: 10.1091/mbc.e20-11-0688
Lihua He 1 , Andrew S Kennedy 1 , Scott Houck 1 , Andrei Aleksandrov 1 , Nancy L Quinney 1 , Alexandra Cyr-Scully 1 , Deborah M Cholon 1 , Martina Gentzsch 1 , Scott H Randell 1 , Hong Yu Ren 1 , Douglas M Cyr 1
Affiliation  

The transmembrane Hsp40 DNAJB12 and cytosolic Hsp70 cooperate on the ER's cytoplasmic face to facilitate the triage of nascent polytopic membrane proteins for folding versus degradation. N1303K is a common mutation that causes misfolding of the ion channel CFTR, but unlike F508del-CFTR, biogenic and functional defects in N1303K-CFTR are resistant to correction by folding modulators. N1303K is reported to arrest CFTR folding at a late stage after partial assembly of its N-terminal domains. N1303K-CFTR intermediates are clients of JB12-Hsp70 complexes, maintained in a detergent soluble-state, and have a relatively long 3-hour half-life. ERAD-resistant pools of N1303K-CFTR are concentrated in ER-tubules that associate with autophagy initiation sites containing WIPI1, FlP200, and LC3. Destabilization of N1303K-CFTR or depletion of JB12 prevents entry of N1303K-CFTR into the membranes of ER-connected phagophores and traffic to autolysosomes. In contrast, the stabilization of intermediates with the modulator VX-809 promotes the association of N1303K-CFTR with autophagy initiation machinery. N1303K-CFTR is excluded from the ER-exit sites, and its passage from the ER to autolysosomes does not require ER-phagy receptors. DNAJB12 operates in biosynthetically active ER-microdomains to triage membrane protein intermediates in a conformation-specific manner for secretion versus degradation via ERAD or selective-ER-associated autophagy.



中文翻译:

DNAJB12 和 Hsp70 分类阻止 N1303K-CFTR 的内质网相关自噬中间体

跨膜 Hsp40 DNAJB12 和胞质 Hsp70 在 ER 的细胞质表面上合作,以促进新生多面体膜蛋白的折叠和降解分类。N1303K 是导致离子通道 CFTR 错误折叠的常见突变,但与 F508del-CFTR 不同,N1303K-CFTR 中的生物和功能缺陷无法通过折叠调节剂进行纠正。据报道,N1303K 在其 N 端结构域部分组装后的后期阶段阻止 CFTR 折叠。N1303K-CFTR 中间体是 JB12-Hsp70 复合物的客户,保持在洗涤剂可溶状态,并且具有相对较长的 3 小时半衰期。N1303K-CFTR 的 ERAD 抗性库集中在与包含 WIPI1、FlP200 和 LC3 的自噬起始位点相关的 ER 小管中。N1303K-CFTR 的不稳定或 JB12 的耗尽会阻止 N1303K-CFTR 进入 ER 连接的吞噬团的膜并进入自溶酶体。相反,调节剂 VX-809 稳定中间体可促进 N1303K-CFTR 与自噬启动机制的结合。N1303K-CFTR 被排除在 ER 出口位点之外,并且其从 ER 到自溶酶体的通道不需要 ER 吞噬受体。DNAJB12 在具有生物合成活性的 ER 微域中发挥作用,以构象特异性方式对膜蛋白中间体进行分类,以便通过 ERAD 或选择性 ER 相关自噬进行分泌或降解。

更新日期:2021-02-04
down
wechat
bug