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  3. ASK1-Mediated Phosphorylation Blocks HDAC6 Ubiquitination and Degradation to Drive the Disassembly of Photoreceptor Connecting Cilia

ASK1-Mediated Phosphorylation Blocks HDAC6 Ubiquitination and Degradation to Drive the Disassembly of Photoreceptor Connecting Cilia

  • Dev Cell. 2020 May 4;53(3):287-299.e5. doi: 10.1016/j.devcel.2020.03.010.
Jie Ran 1,  Min Liu 2,  Jie Feng 3,  Haixia Li 1,  Huixian Ma 1,  Ting Song 1,  Yu Cao 1,  Peng Zhou 1,  Yuhan Wu 1,  Yunfan Yang 3,  Yang Yang 3,  Fan Yu 3,  Heng Guo 1,  Liang Zhang 1,  Songbo Xie 1,  Dengwen Li 3,  Jinmin Gao 1,  Xiaomin Zhang 4,  Xueliang Zhu 5,  Jun Zhou 6
Affiliations

Affiliations

  • 1 Institute of Biomedical Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life Sciences, Shandong Normal University, Jinan 250014, China.
  • 2 Institute of Biomedical Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life Sciences, Shandong Normal University, Jinan 250014, China. Electronic address: minliu@sdnu.edu.cn.
  • 3 State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
  • 4 Eye Institute, School of Optometry and Ophthalmology, Tianjin Medical University Eye Hospital, Tianjin 300384, China.
  • 5 State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
  • 6 Institute of Biomedical Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life Sciences, Shandong Normal University, Jinan 250014, China; State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China. Electronic address: junzhou@sdnu.edu.cn.
PMID: 32275885 DOI: 10.1016/j.devcel.2020.03.010
Abstract

Retinopathy of prematurity (ROP) is a leading cause of childhood blindness. However, the pathogenesis and molecular mechanisms underlying ROP remain elusive. Herein, using the oxygen-induced retinopathy (OIR) mouse model of ROP, we demonstrate that disassembly of photoreceptor connecting cilia is an early event in response to oxygen changes. Histone deacetylase 6 (HDAC6) is upregulated in the retina of OIR mice and accumulates in the transition zone of connecting cilia. We also show that in response to oxygen changes, Apoptosis signal-regulating kinase 1 (ASK1) is activated and phosphorylates HDAC6, blocking its ubiquitination by von Hippel-Lindau and subsequent degradation by the Proteasome. Moreover, depletion of HDAC6 or inhibition of the ASK1/HDAC6 axis protects mice from oxygen-change-induced pathological changes of photoreceptors. These findings reveal a critical role for ASK1/HDAC6-mediated connecting cilium disassembly in the OIR mouse model of ROP and suggest a potential value of ASK1/HDAC6-targeted agents for prevention of this disease.

Keywords

apoptosis signal-regulating kinase 1; connecting cilium; histone deacetylase 6; oxygen-induced retinopathy; phosphorylation; photoreceptor; proteasome; retina; retinopathy of prematurity; ubiquitination.

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