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

Developmental cell 2020 May 04

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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. Copyright © 2020 Elsevier Inc. All rights reserved.

Citation

Jie Ran, Min Liu, Jie Feng, Haixia Li, Huixian Ma, Ting Song, Yu Cao, Peng Zhou, Yuhan Wu, Yunfan Yang, Yang Yang, Fan Yu, Heng Guo, Liang Zhang, Songbo Xie, Dengwen Li, Jinmin Gao, Xiaomin Zhang, Xueliang Zhu, Jun Zhou. ASK1-Mediated Phosphorylation Blocks HDAC6 Ubiquitination and Degradation to Drive the Disassembly of Photoreceptor Connecting Cilia. Developmental cell. 2020 May 04;53(3):287-299.e5