Glutamylation imbalance impairs the molecular architecture of the photoreceptor cilium.
Details
Serval ID
serval:BIB_DF8C1BC82CBD
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Glutamylation imbalance impairs the molecular architecture of the photoreceptor cilium.
Journal
The EMBO journal
ISSN
1460-2075 (Electronic)
ISSN-L
0261-4189
Publication state
Published
Issued date
12/2024
Peer-reviewed
Oui
Volume
43
Number
24
Pages
6679-6704
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Abstract
Microtubules, composed of conserved α/β-tubulin dimers, undergo complex post-translational modifications (PTMs) that fine-tune their properties and interactions with other proteins. Cilia exhibit several tubulin PTMs, such as polyglutamylation, polyglycylation, detyrosination, and acetylation, with functions that are not fully understood. Mutations in AGBL5, which encodes the deglutamylating enzyme CCP5, have been linked to retinitis pigmentosa, suggesting that altered polyglutamylation may cause photoreceptor cell degeneration, though the underlying mechanisms are unclear. Using super-resolution ultrastructure expansion microscopy (U-ExM) in mouse and human photoreceptor cells, we observed that most tubulin PTMs accumulate at the connecting cilium that links outer and inner photoreceptor segments. Mouse models with increased glutamylation (Ccp5 <sup>-/-</sup> and Ccp1-/-) or loss of tubulin acetylation (Atat1-/-) showed that aberrant glutamylation, but not acetylation loss, disrupts outer segment architecture. This disruption includes exacerbation of the connecting cilium, loss of the bulge region, and destabilization of the distal axoneme. Additionally, we found significant impairment in tubulin glycylation, as well as reduced levels of intraflagellar transport proteins and of retinitis pigmentosa-associated protein RPGR. Our findings indicate that proper glutamylation levels are crucial for maintaining the molecular architecture of the photoreceptor cilium.
Keywords
Animals, Mice, Humans, Tubulin/metabolism, Protein Processing, Post-Translational, Cilia/metabolism, Cilia/ultrastructure, Acetylation, Mice, Knockout, Retinitis Pigmentosa/metabolism, Retinitis Pigmentosa/genetics, Retinitis Pigmentosa/pathology, Peptide Synthases/metabolism, Peptide Synthases/genetics, Photoreceptor Connecting Cilium/metabolism, Expansion Microscopy, Glutamylation, Photoreceptor Cell Cilium, Post-translational Modifications, Retinitis Pigmentosa
Pubmed
Web of science
Create date
18/11/2024 13:07
Last modification date
25/02/2025 8:20