DNAJB12 and Hsp70 triage arrested intermediates of N1303K-CFTR for endoplasmic reticulum-associated autophagy.
DNAJB12 and Hsp70 triage arrested intermediates of N1303K-CFTR for endoplasmic reticulum-associated autophagy.
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DOI：
10.1091/mbc.e20-11-0688
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发表时间：
2021-04-01
影响因子：
3.3
通讯作者：
Cyr DM
中科院分区：
文献类型：
--
作者：
He L;Kennedy AS;Houck S;Aleksandrov A;Quinney NL;Cyr-Scully A;Cholon DM;Gentzsch M;Randell SH;Ren HY;Cyr DM
跨膜Hsp 40 DNAJB 12和胞质Hsp 70在内质网（ER）的胞质面上合作以促进新生多位膜蛋白的分类以用于折叠与降解。N1303 K是导致离子通道CFTR错误折叠的常见突变，但与F508 del-CFTR不同，N1303 K-CFTR中的生物和功能缺陷对折叠调节剂的校正具有抗性。据报道，N1303 K在其N-末端结构域部分组装后的后期阶段阻止CFTR折叠。N1303 K-CFTR中间体是JB 12-Hsp 70复合物的客户，保持在洗涤剂可溶的状态，并且具有相对长的3小时半衰期。N1303 K-CFTR的ER相关降解（ERAD）抗性池集中在与含有WIPI 1、FlP 200和LC 3的自噬起始位点相关的ER小管中。N1303 K-CFTR的去稳定化或JB 12的消耗阻止N1303 K-CFTR进入ER连接的吞噬细胞的膜和运输到自溶酶体。相反，用调节剂VX-809稳定中间体促进N1303 K-CFTR与自噬起始机制的关联。N1303 K-CFTR被排除在ER-出口位点之外，并且其从ER到自体溶酶体的通道不需要ER-吞噬受体。DNAJB 12在生物合成活性ER微结构域中起作用，以构象特异性的方式对膜蛋白中间体进行分类，以用于通过ERAD或选择性ER相关的自噬进行分泌与降解。
The transmembrane Hsp40 DNAJB12 and cytosolic Hsp70 cooperate on the endoplasmic reticulum’s (ER) 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-h half-life. ER-associated degradation (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.