title: ARF-mediated SUMOylation of Apak antagonizes ubiquitylation and promotes its nucleolar accumulation to inhibit 47S pre-rRNA synthesis.
abstract: Ribosomes are among the most fundamental molecular machines in all cells, as they are required for protein synthesis. Most structural rRNA components are generated in the nucleolus and assembled into pre-ribosomal particles. Here we show Apak, a previously identified p53 inhibitor, as a novel ribosomal stress response protein. In unstressed cells, Apak is bound to the deSUMOylase SENP1 in the nucleoplasm and targeted for proteasomal degradation by MDM2 ubiquitin ligase. Upon ribosomal stress, SENP1 dissociates from Apak and the tumor suppressor protein ARF couples Ubc9 with Apak to promote Apak SUMOylation on zinc fingers. This results in Apak protein stabilization and translocation to the nucleolus, where Apak inhibits the pre-rRNA synthesis. These findings provide a molecular mechanism whereby ARF coordinates Apak to regulate ribosome biogenesis upon cellular stress.
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Anhui Medical University, Hefei 230032, China.
authors.forename: Siying
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Anhui Medical University, Hefei 230032, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Scientific Research, Xiang-Ya Hospital, Central South University, Changsha 410008, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China Department of Biochemistry and Molecular Biology, Anhui Medical University, Hefei 230032, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Kong
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.
authors.forename: Guichun
authors.initials: G
authors.lastname: Xing
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China zhanglq@nic.bmi.ac.cn hefc@nic.bmi.ac.cn.
authors.forename: Fuchu
authors.initials: F
authors.lastname: He
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China zhanglq@nic.bmi.ac.cn hefc@nic.bmi.ac.cn.
authors.forename: Lingqiang
authors.initials: L
authors.lastname: Zhang
mesh_terms: D021581:Active Transport, Cell Nucleus; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D002466:Cell Nucleolus / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D055550:Protein Stability; D012322:RNA Precursors / Q000096:biosynthesis* / Q000235:genetics; D012335:RNA, Ribosomal / Q000096:biosynthesis* / Q000235:genetics; D058207:Sumoylation; D025803:Tumor Suppressor Protein p14ARF / Q000502:physiology*; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D051017:Apoptosis Regulatory Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D012322:RNA Precursors; D012335:RNA, Ribosomal; C088179:RNA, ribosomal, 45S; D025803:Tumor Suppressor Protein p14ARF; C540923:ZNF420 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D000098843:Ubiquitin-Conjugating Enzyme UBC9
keywords: ARF; Apak; SUMOylation; nucleolar stress; nucleolus