AAA-ATPase p97/Cdc48p, a cytosolic chaperone required for endoplasmic reticulum-associated protein degradation
AAA-ATPase p97/Cdc48p, a cytosolic chaperone required for endoplasmic reticulum-associated protein degradation
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DOI：
10.1128/mcb.22.2.626-634.2002
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发表时间：
2002-01-01
影响因子：
5.3
通讯作者：
Bar-Nun, S
中科院分区：
文献类型：
--
作者：
Rabinovich, E;Kerem, A;Bar-Nun, S
内质网相关降解（ERAD）处理分泌途径中的异常蛋白。ERAD的蛋白质底物通过Sec61p易位从内质网转移到细胞质，在那里它们被蛋白酶体泛素化和降解。由于Sec61p通道也负责新生蛋白的进口，这种双向通道应该是协调的，可能是由分子伴侣。在这里，我们暗示细胞质伴侣aaa - atp酶p97/Cdc48p参与ERAD。我们发现哺乳动物p97及其酵母同源物Cdc48p与两种ERAD底物（B淋巴细胞分泌免疫球蛋白M和酵母分泌6myc-Hmg2p）的复合物存在关联。在条件cdc48酵母突变体中，膜6myc-Hmg2p和可溶性管腔CPY*这两种短寿命ERAD底物明显稳定。当Cdc48p不起作用时，内质网中ERAD底物的积累强调了Cdc48p参与错位的作用，这是通过未折叠蛋白反应的激活来监测的。我们提出p97/Cdc48p在ERAD中的作用，通过其潜在的展开酶活性和多泛素结合能力，是在内质网的细胞质面起作用，并伴随ERAD底物的错位并将其呈现给蛋白酶体。
Endoplasmic reticulum-associated degradation (ERAD) disposes of aberrant proteins in the secretory pathway. Protein substrates of ERAD are dislocated via the Sec61p translocon from the endoplasmic reticulum to the cytosol, where they are ubiquitinated and degraded by the proteasome. Since the Sec61p channel is also responsible for import of nascent proteins, this bidirectional passage should be coordinated, probably by molecular chaperones. Here we implicate the cytosolic chaperone AAA-ATPase p97/Cdc48p in ERAD. We show the association of mammalian p97 and its yeast homologue Cdc48p in complexes with two respective ERAD substrates, secretory immunoglobulin M in B lymphocytes and 6myc-Hmg2p in yeast. The membrane 6myc-Hmg2p as well as soluble lumenal CPY*, two short-lived ERAD substrates, are markedly stabilized in conditional cdc48 yeast mutants. The involvement of Cdc48p in dislocation is underscored by the accumulation of ERAD substrates in the endoplasmic reticulum when Cdc48p fails to function, as monitored by activation of the unfolded protein response. We propose that the role of p97/Cdc48p in ERAD, provided by its potential unfoldase activity and multiubiquitin binding capacity, is to act at the cytosolic face of the endoplasmic reticulum and to chaperone dislocation of ERAD substrates and present them to the proteasome.