Journal article
The myosin-tail homology domain of centrosomal protein 290 is essential for protein confinement between the inner and outer segments in photoreceptors
The Journal of biological chemistry, Vol.294(50), pp.19119-19136
12/13/2019
DOI: 10.1074/jbc.RA119.009712
PMCID: PMC6916492
PMID: 31694913
Abstract
Mutations in the centrosomal protein 290 (CEP290) gene cause various ciliopathies involving retinal degeneration. CEP290 proteins localize to the ciliary transition zone and are thought to act as a gatekeeper that controls ciliary protein trafficking. However, precise roles of CEP290 in photoreceptors and pathomechanisms of retinal degeneration in CEP290-associated ciliopathies are not sufficiently understood. Using conditional Cep290 mutant mice, in which the C-terminal myosin-tail homology domain of CEP290 is disrupted after the connecting cilium is assembled, we show that this domain is essential for protein confinement between the inner and the outer segments. Upon disruption of the myosin-tail homology domain, inner segment plasma membrane proteins, including syntaxin 3 (STX3), synaptosome-associated protein 25 (SNAP25), and interphotoreceptor matrix proteoglycan 2 (IMPG2), rapidly accumulated in the outer segment. In contrast, localization of endomembrane proteins was not altered. Trafficking and confinement of most outer segment-resident proteins appeared to be unaffected or only minimally affected in Cep290 mutant mice. One notable exception was rhodopsin (RHO), which severely mislocalized to inner segments during the initial stage of degeneration. Similar mislocalization phenotypes were observed in Cep290rd16 mice. These results suggest that a failure of protein confinement at the connecting cilium and consequent accumulation of inner segment membrane proteins in the outer segment, along with insufficient RHO delivery, is part of the disease mechanisms that cause retinal degeneration in CEP290-associated ciliopathies. Our study provides insights into the pathomechanisms of retinal degenerations associated with compromised ciliary gates.
Details
- Title: Subtitle
- The myosin-tail homology domain of centrosomal protein 290 is essential for protein confinement between the inner and outer segments in photoreceptors
- Creators
- Poppy Datta - University of IowaBrandon Hendrickson - University of IowaSarah Brendalen - University of IowaAvri Ruffcorn - University of IowaSeongjin Seo - University of Iowa
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.294(50), pp.19119-19136
- DOI
- 10.1074/jbc.RA119.009712
- PMID
- 31694913
- PMCID
- PMC6916492
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- Elsevier Inc
- Grant note
- R01-EY022616 / National Institutes of Health
- Language
- English
- Date published
- 12/13/2019
- Academic Unit
- Ophthalmology and Visual Sciences
- Record Identifier
- 9984187229702771
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