Ubx4 Modulates Cdc48 Activity and Influences Degradation of Misfolded Proteins of the Endoplasmic Reticulum
Ubx4 Modulates Cdc48 Activity and Influences Degradation of Misfolded Proteins of the Endoplasmic Reticulum
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DOI：
10.1074/jbc.m809282200
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发表时间：
2009-06-12
影响因子：
4.8
通讯作者：
Wolf, Dieter H.
中科院分区：
文献类型：
--
作者：
Alberts, Sven M.;Sonntag, Caroline;Wolf, Dieter H.
分泌途径中的错误折叠蛋白在内质网（ER）中被识别，逆转位到细胞质中，并被泛素-蛋白酶体系统降解。在逆转位和多聚泛素化之后，它们通过由AAA ATP酶Cdc 48（哺乳动物中的p97）、Ufd 1和Np 14组成的复合物从ER膜的胞质侧提取。该复合物将错误折叠的蛋白质递送至蛋白酶体进行最终降解。提取，交付和处理ERAD（ER相关降解）底物的蛋白酶体需要额外的辅因子Cdc 48。在这里，我们表征的UBX域包含蛋白Ubx 4（Cui 1）作为一个关键因素的降解polyubiquitinated蛋白通过ERAD。Ubx 4调节Cdc 48-Ufd 1 Np 14复合物以保证其正确功能。Ubx 4的突变变体导致错误折叠蛋白质的降解缺陷和与Cdc 48结合的多聚泛素化蛋白质的积累。我们展示了Ubx 4的UBX域对其在ERAD中的功能的要求。观察到Ubx 2和Ubx 4没有在与Cdc 48的一个复合物中一起发现，这表明在调节ERAD中Cdc 48的活性和定位中有几个不同的步骤。
Misfolded proteins of the secretory pathway are recognized in the endoplasmic reticulum (ER), retrotranslocated into the cytoplasm, and degraded by the ubiquitin-proteasome system. Right after retrotranslocation and polyubiquitination, they are extracted from the cytosolic side of the ER membrane through a complex consisting of the AAA ATPase Cdc48 (p97 in mammals), Ufd1, and Npl4. This complex delivers misfolded proteins to the proteasome for final degradation. Extraction, delivery, and processing of ERAD (ER-associated degradation) substrates to the proteasome requires additional cofactors of Cdc48. Here we characterize the UBX domain containing protein Ubx4 (Cui1) as a crucial factor for the degradation of polyubiquitinated proteins via ERAD. Ubx4 modulates the Cdc48-Ufd1Npl4 complex to guarantee its correct function. Mutant variants of Ubx4 lead to defective degradation of misfolded proteins and accumulation of polyubiquitinated proteins bound to Cdc48. We show the requirement of the UBX domain of Ubx4 for its function in ERAD. The observation that Ubx2 and Ubx4 are not found together in one complex with Cdc48 suggests several distinct steps in modulating the activity and localization of Cdc48 in ERAD.