微管蛋白过度谷氨酰化通过破坏纤毛结构完整性和蛋白转运异常导致视网膜变性
Year: 2026
Type: article
Abstract: Tubulin post-translational modifications confer diverse functions to microtubules, with polyglutamylation representing a dynamic modification governed by coordinated glutamylation and deglutamylation. AGBL5 functions as a deglutamylase that removes glutamate residues at branch points within polyglutamate chains. While pathogenic variants in human AGBL5 are associated with retinitis pigmentosa, the underlying mechanism remains poorly defined. In the present study, an Agbl5 knockout mouse model was established and exhibited pronounced tubulin hyperglutamylation in photoreceptors, followed by progressive retinal degeneration. Transcriptomic profiling identified widespread disruption of ciliary function in Agbl5 knockout mice. Ultrastructural analysis by transmission electron microscopy revealed an impaired inner scaffold within the connecting cilium. Consistent with this defect, key phototransduction proteins were mislocalized or down-regulated in both mutant rod and cone photoreceptors, accompanied by severe disorganization of outer segment disk membranes. Immunofluorescence further demonstrated impaired recruitment of IFT88, kinesin-II, and dynein-2 to the CC, suggesting defective intraflagellar transport. Collectively, these findings indicate that AGBL5-dependent tubulin glutamylation homeostasis is essential for photoreceptor survival through preservation of CC architecture and normal protein trafficking mediated by intraflagellar transport.
Source: 动物学研究
Authors: Wang Hao-Lin, 电子科技大学医学院四川省人民医院检验科, 四川省遗传疾病重点实验室, 四川 成都 610072, 中国, Wang Ting, Zhen Fang-Yuan, Lin Yong-Qiong, Tong Ying-Jie, Wu Jia-Hui, Guo Jia-Xin, Wang Jia-Jia, Dong Shu-Qian, Janke Carsten, M. Magiera Maria, Zhang Hou-Bin, Zou Tong-Dan, 中山大学眼科中心国家重点实验室, 广东 广州市 510060, 中国, 郑州大学第一附属医院眼科, 河南 郑州 450052, 中国, Université Paris-Saclay, Orsay, CNRS UMR3348, France, 中国医学科学院防盲研究单元(2019RU026), 四川省医学科学院・四川省人民医院, 四川 成都 610072, 中国, Université Paris-Saclay, Orsay, CNRS UMR3348, France
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W7128491012
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