The Dfm1 Derlin Is Required for ERAD Retrotranslocation of Integral Membrane Proteins.
The Dfm1 Derlin Is Required for ERAD Retrotranslocation of Integral Membrane Proteins.
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Dfm1 Derlin 是完整膜蛋白 ERAD 逆转位所必需的。
DOI：
10.1016/j.molcel.2018.02.014
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发表时间：
2018
期刊：
影响因子：
16
通讯作者：
Hampton,RandolphY
中科院分区：
文献类型：
--
作者：
Neal,Sonya;Jaeger,PhilippA;Duttke,SaschaH;Benner,Christopher;Glass,ChristopherK;Ideker,Trey;Hampton,RandolphY
内质网（ER）相关降解（ERAD）通过泛素-蛋白酶体途径从内质网膜和管腔中去除错误折叠的蛋白质。泛素化底物到细胞质的反转录易位是ERAD的普遍特征，需要Cdc48 aaa - atp酶。尽管付出了巨大的努力，内质网的退出机制，特别是对于整体膜（ERAD-M）底物，仍然不清楚。利用独立于已知ERAD因子进行正常逆转录的自泛素化底物（SUS）和新的SPOCK （single plate orf compendium kit）微文库查询所有酵母基因，我们发现rhomboid derlin Dfm1是HRD和DOA ERAD通路整体膜底物逆转录所必需的。Dfm1以其独特的SHP基序将Cdc48招募到内质网膜上，并通过其保守的菱形基序催化底物提取。令人惊讶的是，dfm1Δcan经历了快速的抑制，恢复了野生型的adr - m。这一意想不到的抑制解释了早期的研究排除了Dfm1，并揭示了一个辅助的需要Hrd1的rad - m逆转录途径。
Endoplasmic reticulum (ER)-associated degradation (ERAD) removes misfolded proteins from the ER membrane and lumen by the ubiquitin-proteasome pathway. Retrotranslocation of ubiquitinated substrates to the cytosol is a universal feature of ERAD that requires the Cdc48 AAA-ATPase. Despite intense efforts, the mechanism of ER exit, particularly for integral membrane (ERAD-M) substrates, has remained unclear. Using a self-ubiquitinating substrate (SUS), which undergoes normal retrotranslocation independently of known ERAD factors, and the new SPOCK (single plate orf compendium kit) micro-library to query all yeast genes, we found the rhomboid derlin Dfm1 was required for retrotranslocation of both HRD and DOA ERAD pathway integral membrane substrates. Dfm1 recruited Cdc48 to the ER membrane with its unique SHP motifs, and it catalyzed substrate extraction through its conserved rhomboid motifs. Surprisingly,dfm1Δcan undergo rapid suppression, restoring wild-type ERAD-M. This unexpected suppression explained earlier studies ruling out Dfm1, and it revealed an ancillary ERAD-M retrotranslocation pathway requiring Hrd1.