Ubiquitin Linkage Specificity of Deubiquitinases Determines Cyclophilin Nuclear Localization and Degradation
Yanchang Li,
Qiuyan Lan,
Yuan Gao,
Cong Xu,
Zhongwei Xu,
Yihao Wang,
Lei Chang,
Junzhu Wu,
Zixin Deng,
Fuchu He,
Daniel Finley,
Ping Xu
Affiliations
Yanchang Li
State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Research Unit of Proteomics & Research and Development of New Drug of Chinese Academy of Medical Sciences, Beijing Institute of Lifeomics, 38 Science Park Road, Beijing 102206, China
Qiuyan Lan
School of Basic Medical Science, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery of Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
Yuan Gao
State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Research Unit of Proteomics & Research and Development of New Drug of Chinese Academy of Medical Sciences, Beijing Institute of Lifeomics, 38 Science Park Road, Beijing 102206, China
Cong Xu
State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Research Unit of Proteomics & Research and Development of New Drug of Chinese Academy of Medical Sciences, Beijing Institute of Lifeomics, 38 Science Park Road, Beijing 102206, China
Zhongwei Xu
State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Research Unit of Proteomics & Research and Development of New Drug of Chinese Academy of Medical Sciences, Beijing Institute of Lifeomics, 38 Science Park Road, Beijing 102206, China
Yihao Wang
State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Research Unit of Proteomics & Research and Development of New Drug of Chinese Academy of Medical Sciences, Beijing Institute of Lifeomics, 38 Science Park Road, Beijing 102206, China
Lei Chang
State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Research Unit of Proteomics & Research and Development of New Drug of Chinese Academy of Medical Sciences, Beijing Institute of Lifeomics, 38 Science Park Road, Beijing 102206, China
Junzhu Wu
School of Basic Medical Science, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery of Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
Zixin Deng
School of Basic Medical Science, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery of Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
Fuchu He
State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Research Unit of Proteomics & Research and Development of New Drug of Chinese Academy of Medical Sciences, Beijing Institute of Lifeomics, 38 Science Park Road, Beijing 102206, China
Daniel Finley
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
Ping Xu
State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Research Unit of Proteomics & Research and Development of New Drug of Chinese Academy of Medical Sciences, Beijing Institute of Lifeomics, 38 Science Park Road, Beijing 102206, China; School of Basic Medical Science, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery of Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China; Guizhou University School of Medicine, Guiyang 550025, China; Second Clinical Medicine Collage, Guangzhou University Chinese Medicine, Guangzhou 510006, China; Corresponding author
Summary: Ubiquitin chain specificity has been described for some deubiquitinases (DUBs) but lacks a comprehensive profiling in vivo. We used quantitative proteomics to compare the seven lysine-linked ubiquitin chains between wild-type yeast and its 20 DUB-deletion strains, which may reflect the linkage specificity of DUBs in vivo. Utilizing the specificity and ubiquitination heterogeneity, we developed a method termed DUB-mediated identification of linkage-specific ubiquitinated substrates (DILUS) to screen the ubiquitinated lysine residues on substrates modified with certain chains and regulated by specific DUB. Then we were able to identify 166 Ubp2-regulating substrates with 244 sites potentially modified with K63-linked chains. Among these substrates, we further demonstrated that cyclophilin A (Cpr1) modified with K63-linked chain on K151 site was regulated by Ubp2 and mediated the nuclear translocation of zinc finger protein Zpr1. The K48-linked chains at non-K151 sites of Cpr1 were mainly regulated by Ubp3 and served as canonical signals for proteasome-mediated degradation. : Molecular Biology; Omics Subject Areas: Molecular Biology, Omics
