Regulators of tubulin polyglutamylation control nuclear shape and cilium disassembly by balancing microtubule and actin assembly  

作　　者：Lei Wang Sharad C.Paudyal Yuchen Kang Mikito Owa Feng-Xia Liang Alexander Spektor Holger Knaut Irma Sánchez Brian D.Dynlacht 

机构地区：[1]Department of Pathology,New York University Cancer Institute,New York University School of Medicine,New York,NY,USA [2]Department of Radiation Oncology,Dana-Farber Cancer Institute,Brigham and Women’s Hospital,Harvard Medical School,Boston,MA,USA [3]Microscopy Laboratory,Division of Advanced Research Technologies,NYU Langone Health,New York,NY,USA [4]Skirball Institute of Biomolecular Medicine,New York University School of Medicine,New York,NY,USA

出　　处：《Cell Research》2022年第2期190-209,共20页细胞研究（英文版）

基　　金：We are especially grateful to C.Janke for the gift of antibodies and plasmids and advice about polyglutamylation experiments and reagents.We thank NYULH DART Microscopy Laboratory Chris Petzold,Yan Deng and Kristen Dancel-Manning for assistance with CLEM work,and this core is partially funded by NYU Cancer Center Support Grant NIH/NCI P30CA016087;We thank B.Ueberheide and the NYU Langone’s Proteomics Laboratory for assistance with MS analysis.The Proteomics Laboratory is supported in part by NYU Langone Health and the Laura and Isaac Perlmutter Cancer Center support grant P30CA016087 from the National Cancer Institute.The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.We thank D.-S.Lim,J.Kim,Y.Lin,J.I.Cheeseman,K.Ikegami,S.Mitsutoshi and A.Lennon-Duménil for the generous gifts of plasmids and antibodies detailed in Materials and methods.Work in H.Knaut’s laboratory was supported by R01NS102322;Work in BDD’s laboratory was supported by 9R01GM120776;a DOD prostate cancer postdoctoral training award W81XWH-16-1-0392 to L.W.

摘　　要：Cytoskeletal networks play an important role in regulating nuclear morphology and ciliogenesis.However,the role of microtubule(MT)post-translational modifications in nuclear shape regulation and cilium disassembly has not been explored.Here we identified a novel regulator of the tubulin polyglutamylase complex(TPGC),C11ORF49/CSTPP1,that regulates cytoskeletal organization,nuclear shape,and cilium disassembly.Mechanistically,loss of C11ORF49/CSTPP1 impacts the assembly and stability of the TPGC,which modulates long-chain polyglutamylation levels on microtubules(MTs)and thereby balances the binding of MT-associated proteins and actin nucleators.As a result,loss of TPGC leads to aberrant,enhanced assembly of MTs that penetrate the nucleus,which in turn leads to defects in nuclear shape,and disorganization of cytoplasmic actin that disrupts the YAP/TAZ pathway and cilium disassembly.Further,we showed that C11ORF49/CSTPP1-TPGC plays mechanistically distinct roles in the regulation of nuclear shape and cilium disassembly.Remarkably,disruption of C11ORF49/CSTPP1-TPGC also leads to developmental defects in vivo.Our findings point to an unanticipated nexus that links tubulin polyglutamylation with nuclear shape and ciliogenesis.

关 键 词：thereby finding shape 

分 类 号：O57[理学—粒子物理与原子核物理]