Developmental cell, 2020-05, Vol.53 (3), p.287-299.e5
2020
Details
- Autor(en) / Beteiligte
- Titel
- ASK1-Mediated Phosphorylation Blocks HDAC6 Ubiquitination and Degradation to Drive the Disassembly of Photoreceptor Connecting Cilia
- Ist Teil von
- Developmental cell, 2020-05, Vol.53 (3), p.287-299.e5
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2020
- Link zum Volltext
- Quelle
- ScienceDirect
- Beschreibungen/Notizen
- 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. [Display omitted] •HDAC6 upregulation drives connecting cilium disassembly in OIR mouse model of ROP•Oxygen changes activate ASK1 to phosphorylate HDAC6 in the OIR mouse retina•HDAC6 phosphorylation blocks its ubiquitination by VHL and proteasomal degradation•Inhibition of ASK1 or HDAC6 protects mice from oxygen-change-induced pathologies Using the oxygen-induced retinopathy (OIR) mouse model for retinopathy of prematurity (ROP), Ran et al. show that oxygen changes trigger ASK1 activation to phosphorylate HDAC6, blocking HDAC6 ubiquitination by VHL and proteasomal degradation. HDAC6 then drives photoreceptor connecting cilium disassembly, which they demonstrate is an early event in OIR pathogenesis.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1534-5807eISSN: 1878-1551DOI: 10.1016/j.devcel.2020.03.010Titel-ID: cdi_crossref_primary_10_1016_j_devcel_2020_03_010
- Format
- –
- Schlagworte
- Animals, apoptosis signal-regulating kinase 1, Cilia - metabolism, Cilia - pathology, connecting cilium, Female, histone deacetylase 6, Histone Deacetylase 6 - antagonists & inhibitors, Histone Deacetylase 6 - genetics, Histone Deacetylase 6 - metabolism, Male, MAP Kinase Kinase Kinase 5 - genetics, MAP Kinase Kinase Kinase 5 - metabolism, Mice, Mice, Inbred C57BL, Oxygen - toxicity, oxygen-induced retinopathy, Phosphorylation, photoreceptor, Photoreceptor Connecting Cilium - metabolism, Photoreceptor Connecting Cilium - pathology, proteasome, Proteolysis, retina, retinopathy of prematurity, Retinopathy of Prematurity - etiology, Retinopathy of Prematurity - metabolism, Retinopathy of Prematurity - pathology, Ubiquitination