CYLD Maintains Retinal Homeostasis by Deubiquitinating ENKD1 and Promoting the Phagocytosis of Photoreceptor Outer Segments
Phagocytosis of shed photoreceptor outer segments by the retinal pigment epithelium (RPE) is essential for retinal homeostasis. Dysregulation of the phagocytotic process is associated with irreversible retinal degenerative diseases. However, the molecular mechanisms underlying the phagocytic activity of RPE cells remain elusive. In an effort to uncover proteins orchestrating retinal function, the cylindromatosis (CYLD) deubiquitinase is identified as a critical regulator of photoreceptor outer segment phagocytosis. CYLD-deficient mice exhibit abnormal retinal structure and function. Mechanistically, CYLD interacts with enkurin domain containing protein 1 (ENKD1) and deubiquitinates ENKD1 at lysine residues K141 and K242. Deubiquitinated ENKD1 interacts with Ezrin, a membrane-cytoskeleton linker, and stimulates the microvillar localization of Ezrin, which is essential for the phagocytic activity of RPE cells. These findings thus reveal a crucial role for the CYLD-ENKD1-Ezrin axis in regulating retinal homeostasis and may have important implications for the prevention and treatment of retinal degenerative diseases.
Authors
- Jie Ran (ORCID: https://orcid.org/0000-0002-0744-7126)
- Xuemei Wu (ORCID: https://orcid.org/0000-0003-1640-7385)
- Mulin Yang (ORCID: https://orcid.org/0000-0001-9951-0411)
- Quanlong Lü (ORCID: https://orcid.org/0000-0002-4261-5121)
- Jun Zhou (ORCID: https://orcid.org/0000-0001-7858-8260)
- Yunfan Yang (ORCID: https://orcid.org/0000-0002-5266-7208)
- Sei Yoshida (ORCID: https://orcid.org/0000-0002-4771-3900)
- Weishu Wang (ORCID: https://orcid.org/0000-0003-2446-5761)
- Nan Ma (ORCID: https://orcid.org/0000-0003-4006-1003)
- Hanxiao Yin (ORCID: https://orcid.org/0000-0002-6764-8632)
- Dengwen Li (ORCID: https://orcid.org/0000-0002-4573-7191)
- Huijie Hao (ORCID: https://orcid.org/0000-0002-7598-5567)
- Denghui Zhai (ORCID: https://orcid.org/0009-0009-0994-1847)
- Weiwen Bu (ORCID: https://orcid.org/0000-0002-3717-2848)
- Yu Fan (ORCID: https://orcid.org/0000-0002-9917-593X)
- Jia Yang (ORCID: https://orcid.org/0009-0006-1502-9959)
- Te Li (ORCID: https://orcid.org/0000-0002-9007-469X)
- Hua Ni (ORCID: https://orcid.org/0000-0001-9137-3707)
- Ting Song (ORCID: https://orcid.org/0000-0001-5945-6676)
- Song Yang (ORCID: https://orcid.org/0009-0009-7097-4429)
- Min Liu (ORCID: https://orcid.org/0009-0003-8010-3084)
Institutions
- Qingdao University (CN)
- Shandong University (CN)
- Nankai University (CN)
- Shandong Normal University (CN)
- Affiliated Hospital of Qingdao University (CN)
- Tianjin haihe hospital (CN)
- State Key Laboratory of Medicinal Chemical Biology
Publication Details
- Journal
- Advanced Science
- Published
- 2024-10-07
- DOI
- https://doi.org/10.1002/advs.202404067
- Citations
- 6
- Primary Topic
- Retinal Development and Disorders
- Type
- article
- Field-Weighted Citation Impact
- 1.40
Funders
- National Natural Science Foundation of China