Endolysosomal sorting of ubiquitylated caveolin-1 is regulated by VCP and UBXD1 and impaired by VCP disease mutations.
Endolysosomal sorting of ubiquitylated caveolin-1 is regulated by VCP and UBXD1 and impaired by VCP disease mutations.
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DOI：
10.1038/ncb2301
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发表时间：
2011-08-07
影响因子：
21.3
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中科院分区：
文献类型：
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AAA-ATPase VCP/p97与不同的协同因子协同作用，在不同的细胞途径中处理泛素化的蛋白质。VCP错义突变可导致人类全身性退行性疾病，但其分子发病机制尚不清楚。我们使用无偏倚的质谱学方法，鉴定了一个与UBXD1辅因子结合的VCP复合体，它结合了质膜蛋白小窝蛋白-1(Cav1)，其形成被疾病相关突变特异性干扰。我们发现VCP-UBXD1靶向内体上耐十二烷基硫酸钠的高分子量复合体中单一泛素化的Cav1，这些复合体正在内溶体中降解。VCP突变蛋白的表达，VCP的化学抑制，或siRNA介导的UBXD1的耗竭导致培养细胞中扩大的内容体的极限膜上的Cav1转运受阻。在患者肌肉中，肌肉特异性小窝蛋白-3(Caveolin-3)聚集在肌浆池中，并特异性地从肌膜中分离出来。这些结果将VCP的细胞功能扩展到介导内吞途径中泛素化货物的分选，并提示小窝蛋白转运受损可能参与了VCP突变个体的发病机制。
The AAA-ATPase VCP/p97 cooperates with distinct cofactors to process ubiquitinated proteins in different cellular pathways . VCP missense mutations cause a systemic degenerative disease in humans, but the molecular pathogenesis is unclear . We used an unbiased mass spectrometry approach and identified a VCP complex with the UBXD1 cofactor, which binds the plasma membrane protein caveolin-1 (Cav1) and whose formation is specifically disrupted by disease-associated mutations. We show that VCP-UBXD1 targets mono-ubiquitinated Cav1 in SDS-resistant high molecular weight complexes on endosomes, which are en route to degradation in endolysosomes . Expression of VCP mutant proteins, chemical inhibition of VCP, or siRNA-mediated depletion of UBXD1 leads to a block of Cav1 transport at the limiting membrane of enlarged endosomes in cultured cells. In patient muscle, muscle-specific Caveolin-3 (Cav3) accumulates in sarcoplasmic pools and specifically delocalises from the sarcolemma. These results extend the cellular functions of VCP to mediating sorting of ubiquitinated cargo in the endocytic pathway and suggest that impaired trafficking of caveolin may contribute to the pathogenesis in individuals with VCP mutations.
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DOI：
10.1083/jcb.201003086
发表时间：
2010-11-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hayer A;Stoeber M;Ritz D;Engel S;Meyer HH;Helenius A
通讯作者：
Helenius A
影响因子：
7.7
作者：
Fernandez-Saiz, Vanesa;Buchberger, Alexander
通讯作者：
Buchberger, Alexander
影响因子：
64.5
作者：
Rape, M;Hoppe, T;Jentsch, S
通讯作者：
Jentsch, S
影响因子：
82.9
作者：
Iwawaki, T;Akai, R;Miura, M
通讯作者：
Miura, M
影响因子：
64.8
作者：
Ramadan, Kristijan;Bruderer, Roland;Meyer, Hemmo H.
通讯作者：
Meyer, Hemmo H.