Tubulin hyperglutamylation induces retinal degeneration by disrupting ciliary architecture and protein trafficking

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.