Kajimura, N. | bioRxiv Science

bioRxiv2024

Ccrk-Mak/Ick kinase signaling axis is a ciliary transport regulator essential for retinal photoreceptor maintenance

Primary cilia are microtubule-based sensory organelles whose dysfunction leads to ciliopathies in humans. The formation, function, and maintenance of primary cilia depend crucially on intraflagellar transport (IFT); however, the regulatory mechanisms of IFT and their physiological roles are poorly understood. In the current study, we screened and identified that the ciliopathy kinase Mak is a ciliary tip-localized IFT regulator that cooperatively acts with the ciliopathy kinase Ick, an IFT regulator. Simultaneous disruption of Mak and Ick resulted in loss of photoreceptor ciliary axonemes and severe degeneration in the mouse retina. Mak overexpression restored ciliary defects caused by Ick deficiency in cultured cells. Gene delivery of Ick and pharmacological inhibition of FGF receptors, negative regulators of Ick, ameliorated retinal degeneration in Mak-/-mice. In addition, we identified that Ccrk kinase is an upstream activator of Mak and Ick in retinal photoreceptor cells. Furthermore, overexpression of Mak, Ick, and Ccrk and pharmacological inhibition of FGF receptors suppressed ciliopathy-related phenotypes caused by cytoplasmic dynein inhibition in cultured cells. Collectively, our results show that the Ccrk-Mak/Ick axis is an essential IFT regulator crucial for retinal photoreceptor maintenance. This study sheds light on pathological mechanisms underlying retinitis pigmentosa caused by mutations in the human MAK gene and presents activation of Ick as a potential therapeutic approach for this retinal degenerative disease.

developmental biology↗

bioRxiv2021

A novel capsid protein network allows the characteristic inner membrane structure of Marseilleviridae giant viruses

Marseilleviridae is a family of the new order of giant viruses, which exhibit a characteristic inner membrane. Here, we investigated the entire structure of tokyovirus, a species of Marseillevirus at 7.7 [A] resolution using 1 MV high-voltage cryo-EM and single particle analysis. The minor capsid lattice formed by five proteins, shows a novel structure compared to other icosahedral giant viruses. Under the minor capsid proteins, scaffold proteins connect two five-fold vertices and interact with the inner membrane. Previously reported giant viruses utilise "tape measure" proteins, proposed to control its capsid size, which could not be identified in tokyovirus, but scaffold proteins appear to perform a similar role. A density on top of the major capsid protein was identified, which suggested to be a 14kDa glycoprotein. Our observations suggest that the icosahedral particle of Marseilleviridae is constructed with a novel capsid protein network, which allows the characteristic inner membrane structure.

microbiology↗