Systematic proteomics of the VCP-UBXD adaptor network identifies a role for UBXN10 in regulating ciliogenesis.
Systematic proteomics of the VCP-UBXD adaptor network identifies a role for UBXN10 in regulating ciliogenesis.
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DOI：
10.1038/ncb3238
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发表时间：
2015-10
影响因子：
21.3
通讯作者：
Harper JW
中科院分区：
文献类型：
--
作者：
Raman M;Sergeev M;Garnaas M;Lydeard JR;Huttlin EL;Goessling W;Shah JV;Harper JW
AAA-ATP酶VCP（也称为p97或CDC 48）利用ATP水解将泛素化蛋白与其结合伴侣“分离”。VCP通过含有UBX结构域的衔接子发挥作用，这些衔接子提供靶特异性，但对UBXD蛋白的靶点和功能仍知之甚少。通过对人类细胞中UBXD蛋白的系统性蛋白质组学分析，我们揭示了超过195个相互作用蛋白的网络，表明VCP参与了多种细胞途径。我们已经探索了一个这样的复合物之间的一个未研究的适配器UBXN 10和鞭毛内运输B（IFFT-B）复合物，调节顺行运输到纤毛。UBXN 10以VCP依赖的方式定位于纤毛，VCP和UBXN 10都是纤毛发生所需的。VCP的药理学抑制使IFT-B复合物不稳定，并增加了贩运率。斑马鱼胚胎中UBXN 10的缺失导致左右不对称的缺陷，这取决于功能性纤毛。这项研究为探索UBXD蛋白在生物学中的前景提供了资源，并确定了纤毛发生中对VCP-UBXN 10的意外需求。
The AAA-ATPase VCP (also known as p97 or CDC48) uses ATP hydrolysis to “segregate” ubiquitinated proteins from their binding partners. VCP acts via UBX-domain containing adaptors that provide target specificity, but targets and functions of UBXD proteins remain poorly understood. Through systematic proteomic analysis of UBXD proteins in human cells, we reveal a network of over 195 interacting proteins, implicating VCP in diverse cellular pathways. We have explored one such complex between an unstudied adaptor UBXN10 and the intraflagellar transport B (IFT-B) complex, which regulates anterograde transport into cilia. UBXN10 localizes to cilia in a VCP-dependent manner and both VCP and UBXN10 are required for ciliogenesis. Pharmacological inhibition of VCP destabilized the IFT-B complex and increased trafficking rates. Depletion of UBXN10 in zebrafish embryos causes defects in left-right asymmetry, which depends on functional cilia. This study provides a resource for exploring the landscape of UBXD proteins in biology and identifies an unexpected requirement for VCP-UBXN10 in ciliogenesis.