The phosphorylation and dephosphorylation switch of VCP/p97 regulates the architecture of centrosome and spindle

作者全名："Zhu, Kaiyuan; Cai, Yang; Si, Xiaotong; Ye, Zuodong; Gao, Yuanzhu; Liu, Chuang; Wang, Rui; Ma, Zhibin; Zhu, Huazhang; Zhang, Liang; Li, Shengjin; Zhang, Hongmin; Yue, Jianbo"

作者地址："[Zhu, Kaiyuan; Si, Xiaotong; Ye, Zuodong; Wang, Rui; Ma, Zhibin; Zhu, Huazhang; Zhang, Liang; Yue, Jianbo] City Univ Hong Kong, Shenzhen Res Inst, Shenzhen, Peoples R China; [Zhu, Kaiyuan; Si, Xiaotong; Ye, Zuodong; Wang, Rui; Ma, Zhibin; Zhu, Huazhang; Zhang, Liang; Yue, Jianbo] City Univ Hong Kong, Dept Biomed Sci, Hong Kong, Peoples R China; [Cai, Yang; Zhang, Hongmin] Southern Univ Sci & Technol, Dept Biol, Shenzhen 518055, Peoples R China; [Gao, Yuanzhu; Liu, Chuang] Southern Univ Sci & Technol, SUSTech CryoEM Ctr, Dept Biol, Shenzhen 518055, Peoples R China; [Li, Shengjin] Chongqing Med Univ, Affiliated Hosp 2, Chongqing, Peoples R China"

通信作者："Yue, JB (通讯作者)，City Univ Hong Kong, Shenzhen Res Inst, Shenzhen, Peoples R China.; Yue, JB (通讯作者)，City Univ Hong Kong, Dept Biomed Sci, Hong Kong, Peoples R China.; Zhang, HM (通讯作者)，Southern Univ Sci & Technol, Dept Biol, Shenzhen 518055, Peoples R China.; Li, SJ (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Chongqing, Peoples R China."

来源：CELL DEATH AND DIFFERENTIATION

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000782885100002

JCR分区：Q1

影响因子：12.4

年份：2022

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：　

摘要："The proper orientation of centrosome and spindle is essential for genome stability; however, the mechanism that governs these processes remains elusive. Here, we demonstrated that polo-like kinase 1 (Plk1), a key mitotic kinase, phosphorylates residue Thr76 in VCP/p97 (an AAA-ATPase), at the centrosome from prophase to anaphase. This phosphorylation process recruits VCP to the centrosome and in this way, it regulates centrosome orientation. VCP exhibits strong co-localization with Eg5 (a mitotic kinesin motor), at the mitotic spindle, and the dephosphorylation of Thr76 in VCP is required for the enrichment of both VCP and Eg5 at the spindle, thus ensuring proper spindle architecture and chromosome segregation. We also showed that the phosphatase, PTEN, is responsible for the dephosphorylation of Thr76 in VCP; when PTEN was knocked down, the normal spread of VCP from the centrosome to the spindle was abolished. Cryo-EM structures of VCPT76A and VCPT76E, which represent dephosphorylated and phosphorylated states of VCP, respectively, revealed that the Thr76 phosphorylation modulates VCP by altering the inter-domain and inter-subunit interactions, and ultimately the nucleotide-binding pocket conformation. Interestingly, the tumor growth in nude mice implanted with VCPT76A-reconstituted cancer cells was significantly slower when compared with those implanted with VCPWT-reconstituted cancer cells. Collectively, our findings demonstrate that the phosphorylation and dephosphorylation switch of VCP regulates the architecture of centrosome and spindle for faithful chromosome segregation."

基金机构："Hong Kong Research Grant Council [11101717, 11103620]; Ministry of Science and Technology of the People's Republic of China [2019YFA0906000]; NSFC [21778045, 32070702, 82161128014, MRP/064/21, GHP/097/20GD]; Guangdong Science and Technology Program [2017B030301018]; Shenzhen Science and Technology Innovation Committee [SGDX20201103093201010, JSGG20200225150702770, JCYJ20210324134007020, ZDSYS20140509142721429]"

基金资助正文："This work was supported by Hong Kong Research Grant Council grants (11101717 and 11103620 to JY), Ministry of Science and Technology of the People's Republic of China (2019YFA0906000 to HZ), NSFC (21778045, 32070702, and 82161128014 to JY), ITF (MRP/064/21 and GHP/097/20GD to JY), Guangdong Science and Technology Program (2017B030301018 to HZ), Shenzhen Science and Technology Innovation Committee (SGDX20201103093201010, JSGG20200225150702770, and JCYJ20210324134007020 to JY, and ZDSYS20140509142721429 to HZ)."