title: Ubiquitylation of autophagy receptor Optineurin by HACE1 activates selective autophagy for tumor suppression.
abstract: In selective autophagy, receptors are central for cargo selection and delivery. However, it remains yet unclear whether and how multiple autophagy receptors might form complex and function concertedly to control autophagy. Optineurin (OPTN), implicated genetically in glaucoma and amyotrophic lateral sclerosis, was a recently identified autophagy receptor. Here we report that tumor-suppressor HACE1, a ubiquitin ligase, ubiquitylates OPTN and promotes its interaction with p62/SQSTM1 to form the autophagy receptor complex, thus accelerating autophagic flux. Interestingly, the Lys48-linked polyubiquitin chains that HACE1 conjugates onto OPTN might predominantly target OPTN for autophagic degradation. By demonstrating that the HACE1-OPTN axis synergistically suppresses growth and tumorigenicity of lung cancer cells, our findings may open an avenue for developing autophagy-targeted therapeutic intervention into cancer.
authors.affiliation: State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China; Graduate School, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.
authors.forename: Zhengzhao
authors.initials: Z
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China; Graduate School, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai 200032, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China; School of Life Science, Anhui Medical University, Hefei, Anhui 230032, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Gu
authors.affiliation: State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China; Graduate School, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China; Graduate School, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China; Graduate School, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.
authors.forename: Xingxing
authors.initials: X
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China; Graduate School, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.
authors.forename: Meiqiang
authors.initials: M
authors.lastname: Yang
authors.affiliation: School of Life Science, Anhui Medical University, Hefei, Anhui 230032, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Liu
authors.affiliation: School of Life Science, Anhui Medical University, Hefei, Anhui 230032, China.
authors.forename: Libin
authors.initials: L
authors.lastname: Fan
authors.affiliation: Department of Gastroenterology, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai 200032, China.
authors.forename: Shiyao
authors.initials: S
authors.lastname: Chen
authors.affiliation: Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai 200032, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Gastroenterology, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai 200032, China.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.
authors.forename: Kangchen
authors.initials: K
authors.lastname: Ruan
authors.affiliation: Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 800 Xiangyin Road, Shanghai 200433, China.
authors.forename: Shuqun
authors.initials: S
authors.lastname: Cheng
authors.affiliation: Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: The Cancer Institute of New Jersey, Rutgers University, 195 Little Albany Street, New Brunswick, NJ 08903-2681, USA.
authors.forename: Eileen
authors.initials: E
authors.lastname: White
authors.affiliation: State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Ji
authors.affiliation: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Finley
authors.affiliation: State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China; Cancer Research Center, SIBS-Xuhui Central Hospital, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China; Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China. Electronic address: coryhu@sibs.ac.cn.
authors.forename: Ronggui
authors.initials: R
authors.lastname: Hu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004249:DNA Damage; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000517:prevention & control; D008239:Lysine; D008264:Macrophages / Q000201:enzymology; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D011485:Protein Binding; D034622:RNA Interference; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction; D013997:Time Factors; D035582:Transcription Factor TFIIIA / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D005136:Eye Proteins; D006360:Heat-Shock Proteins; C477012:MAP1LC3A protein, human; D026901:Membrane Transport Proteins; D008869:Microtubule-Associated Proteins; C409460:OPTN protein, human; C501288:Optn protein, mouse; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D035582:Transcription Factor TFIIIA; D025521:Tumor Suppressor Proteins; C497506:HACE1 protein, human; C000591483:HACE1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D008239:Lysine