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Ya-Chu Hsu, Jen-Zen Chuang, Ching-Kang Jason Chen, Yu-Ting Yan, Yun-Zheng Le, Ching-Hwa Sung; Molecular regulation in rhodopsin transport. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4377.
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© ARVO (1962-2015); The Authors (2016-present)
Outer segment (OS) is the cilium of retina photoreceptors and contains ~1000 membrane discs to house phototransduction machinery. Mammalian OS turns over every 10 days. Distal discs are shed and phagocytosed by adjacent pigmented epithelia for degradation. Polarized protein transport from cell body to OS in order to assemble new discs is critical to maintain OS homeostasis and photoreceptor health. The molecular mechanism governing OS-directed transport is not fully understood. Previously we demonstrated that SARA, a FYVE finger protein, is required for biogenesis of nascent discs at basal OS in rods. Knocking down Sara functions caused rhodopsin mislocalization in the cell body. Current study is designed to test whether Sara may also be involved in OS delivery of other OS components in addition to rhodopsin. We investigate candidate molecular regulators required for rhodopsin OS delivery.
Conditional SARA-knockout mice were generated to investigate SARA’s function in rods. In vivo retina transfection was used to assess roles of candidate molecules in rhodopsin OS delivery.
Sara rod-knockout (SararodKO) mice underwent slow photoreceptor degeneration within a year. Rod OS was able to form and mature, but photopigment rhodopsin was mislocalized to the inner segment plasma membrane and around the Golgi. RetGC was largely reduced in rod OS. Ultrastructural analysis of OS in SararodKO revealed abnormal vesicular profiles. Rab11+ recycling endosomes in the inner segment was largely diminished upon Sara deletion. Ectopic expression of dominant negative rab11 mutant (S25N) interfered with normal rhodopsin trafficking in vivo. Furthermore, expression of dominant negative dynamin mutant (K44A) caused severe rhodopsin mislocalization throughout the entire rod cell. Our data revealed a novel connection between Sara and recycling endosomes in rhodopsin transport, and suggested a functional role of dynamin in generating rhodopsin vesicular carriers in rod photoreceptors.
Sara is required for proper OS targeting of rhodopsin and RetGC. A functional crosstalk between Sara and rab11 compartments is important for normal rhodopsin trafficking. Our data demonstrated a previously unappreciated role of dynamin in rhodopsin exocytic pathway.
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