Contribution of intraflagellar transport to compartmentalization and maintenance of the photoreceptor cell

• 成果类型: Article
• 署名作者: Lewis, Tylor R.; Castillo, Carson M.; Klementieva, Natalia, V; Hsu, Ying; Hao, Ying; Spencer, William J.; Drack, Arlene, V; Pazour, Gregory J.; Arshavsky, Vadim Y.
• 署名单位: Duke University; University of Iowa; University of Massachusetts System; University of Massachusetts Worcester; Duke University; University of Alabama System; University of Alabama Birmingham; State University of New York (SUNY) System; SUNY Upstate Medical University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10216
• DOI: 10.1073/pnas.2408551121
• 发表日期: 2024-08-20
• 关键词: bardet-biedl syndrome; retinal degeneration; kinesin-ii; heterotrimeric kinesin-2; outer segments; mutant mouse; protein; ciliary; rhodopsin; complex

摘要

The first steps of vision take place in the ciliary outer segment compartment of photoreceptor cells. The protein composition of outer segments is uniquely suited to perform this function. The most abundant among these proteins is the visual pigment, rhodopsin, whose outer segment trafficking involves intraflagellar transport (IFT). Here, we report three major findings from the analysis of mice in which ciliary transport was acutely impaired by conditional knockouts of IFT-B subunits. First, we demonstrate the existence of a sorting mechanism whereby mislocalized rhodopsin is recruited to and concentrated in extracellular vesicles prior to their release, presumably to protect the cell from adverse effects of protein mislocalization. Second, reducing rhodopsin expression significantly delays photoreceptor degeneration caused by IFT disruption, suggesting that controlling rhodopsin levels may be an effective therapy for some cases of retinal degenerative disease. Last, the loss of IFT-B subunits does not recapitulate a phenotype observed in mutants of the BBSome (another ciliary transport protein complex relying on IFT) in which non- ciliary proteins accumulate in the outer segment. Whereas it is widely thought that the role of the BBSome is to primarily participate in ciliary transport, our data suggest that the BBSome has another major function independent of IFT and possibly related to maintaining the diffusion barrier of the ciliary transition zone.