Regulatory mechanisms of ciliary protein transport through Ccrk-Mak/Ick kinase signaling in retinal photoreceptor cells

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• Dr Yamato Maeda, Research fellow, Institute for Protein Research, Osaka University, Japan
• Monday 16 December 2024, 12:00-13:00
• Bryan Matthews Seminar Room, Physiological Laboratory building, Department of Physiology, Development and Neuroscience.

If you have a question about this talk, please contact Keita Tamura.

Primary cilia are hair-like microtubule-based structures whose dysfunction leads to human diseases termed ciliopathies. The formation, function, and maintenance of primary cilia rely on ciliary protein transport systems including lipidated protein intraflagellar targeting (LIFT) and intraflagellar transport (IFT). We previously reported that CUL3 -KLHL18 ubiquitin ligase regulates light-dark adaptation of retinal photoreceptor cells through modulating LIFT (1). However, the regulatory mechanisms underlying ciliary protein transport remain unclear. Here, we identified that the ciliopathy kinase Mak is a ciliary tip-localized IFT regulator that functions with the ciliopathy kinase Ick, as an IFT regulator at ciliary tips. Disruption of both Mak and Ick caused loss of photoreceptor ciliary axonemes and severe progressive retinal degeneration. Gene delivery of Ick and pharmacological activation of Ick with an FGF receptors inhibitor ameliorated ciliopathy-related retinal degeneration in Mak−/− mice. Additionally, we found that Ccrk kinase is an upstream activator of Mak and Ick in retinal photoreceptor cells. This study suggests that the Ccrk-Mak/Ick axis is an IFT turnaround regulator essential for retinal photoreceptor maintenance and presents activation of Ick as a potential therapeutic approach for retinitis pigmentosa caused by MAK mutations (2).

This talk is part of the Keita Tamura Lab @ PDN series.

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• Bryan Matthews Seminar Room, Physiological Laboratory building, Department of Physiology, Development and Neuroscience
• Keita Tamura Lab @ PDN

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