期刊
AUTOPHAGY
卷 14, 期 1, 页码 66-79出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2017.1391970
关键词
autophagy receptor; linear ubiquitin chain; optineurin; TBK1; UBAN domain
类别
资金
- Chinese Academy of Sciences
- Science and Technology Commission of Shanghai Municipality [15JC1400400]
- Thousand Talents Program young investigator award
- National Natural Science Foundation of China [31530041, 21621002, 31470749]
- Chinese Academy of Sciences [XDB20000000]
- China Ministry of Science and Technology Program [2014ZX09102001-002]
- State Key Laboratory of Bioorganic and Natural Products Chemistry
- National Key R& D Program of China [2016YFA0501903, 2013CB836900]
OPTN (optineurin), a ubiquitin-binding scaffold protein, functions as an important macroautophagy/autophagy receptor in selective autophagy processes. Mutations in OPTN have been linked with human neurodegenerative diseases including ALS and glaucoma. However, the mechanistic basis underlying the recognition of ubiquitin by OPTN and its regulation by TBK1-mediated phosphorylation are still elusive. Here, we demonstrate that the UBAN domain of OPTN preferentially recognizes linear ubiquitin chain and forms an asymmetric 2:1 stoichiometry complex with the linear diubiquitin. In addition, our results provide new mechanistic insights into how phosphorylation of UBAN would regulate the ubiquitin-binding ability of OPTN and how disease-associated mutations in the OPTN UBAN domain disrupt its interaction with ubiquitin. Finally, we show that defects in ubiquitin-binding may affect the recruitment of OPTN to linear ubiquitin-decorated mutant Huntington protein aggregates. Taken together, our findings clarify the interaction mode between UBAN and linear ubiquitin chain in general, and expand our knowledge of the molecular mechanism of ubiquitin-decorated substrates recognition by OPTN as well as the pathogenesis of neurodegenerative diseases caused by OPTN mutations.
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