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PMID:28855254

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Citation

Feng, D, Chen, Z, Yang, K, Miao, S, Xu, B, Kang, Y, Xie, H and Zhao, C (2017) The cytoplasmic tail of rhodopsin triggers rapid rod degeneration in kinesin-2 mutants. J. Biol. Chem. 292:17375-17386

Abstract

Photoreceptor degeneration can lead to blindness and represents the most common form of neural degenerative disease worldwide. Although many genes involved in photoreceptor degeneration have been identified, the underlying mechanisms remain to be elucidated. Here we examined photoreceptor development in zebrafish and mutants, which affect two subunits of the kinesin-2 complex. In both mutants, rods degenerated quickly, whereas cones underwent a slow degeneration process. Notably, the photoreceptor defects were considerably more severe in mutants than in mutants. In the cone photoreceptors of mutants, opsin proteins accumulated in the apical region and formed abnormal membrane structures. In contrast, rhodopsins were enriched in the rod cell body membrane and represented the primary reason for rapid rod degeneration in these mutants. Moreover, removal of the cytoplasmic tail of rhodopsin to reduce its function, but not decreasing rhodopsin expression levels, prevented rod degeneration in both and mutants. Of note, overexpression of full-length rhodopsin or its cytoplasmic tail domain, but not of rhodopsin lacking the cytoplasmic tail, exacerbated rod degeneration in mutants, implying an important role of the cytoplasmic tail in rod degeneration. Finally, we showed that the cytoplasmic tail of rhodopsin might trigger rod degeneration through activating the downstream calcium signaling pathway, as drug treatment with inhibitors of intracellular calcium release prevented rod degeneration in mutants. Our results demonstrate a previously unknown function of the rhodopsin cytoplasmic domain during opsin-triggered photoreceptor degeneration and may open up new avenues for managing this disease.

Links

PubMed PMC5655514 Online version:10.1074/jbc.M117.784017

Keywords

Animals; Calcium Signaling; Cell Membrane/genetics; Cell Membrane/metabolism; Kinesin/genetics; Kinesin/metabolism; Mutation; Protein Domains; Retinal Rod Photoreceptor Cells/metabolism; Rhodopsin/genetics; Rhodopsin/metabolism; Zebrafish; Zebrafish Proteins/genetics; Zebrafish Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DANRE:A0A2R8QGI2

involved_in

GO:0060271: cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-180904-4

P

Seeded From UniProt

complete

DANRE:E9QB71

involved_in

GO:0060271: cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-180904-4

P

Seeded From UniProt

complete

DANRE:KIF3B

involved_in

GO:0060271: cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DANRE:KIF3B

involved_in

GO:0042461: photoreceptor cell development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DANRE:KIF3B

involved_in

GO:0060271: cilium assembly

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-GENE-111214-2

P

Seeded From UniProt

complete

DANRE:KIF3B

involved_in

GO:0060271: cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-120327-3

P

Seeded From UniProt

complete

DANRE:Q568I3

involved_in

GO:0060271: cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-180904-4

P

Seeded From UniProt

complete

DANRE:Q6DEG6

involved_in

GO:0060271: cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-180904-4

P

Seeded From UniProt

complete

DANRE:F1QN54

involved_in

GO:0060271: cilium assembly

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-GENE-111214-2

P

Seeded From UniProt

complete

DANRE:F1QN54

involved_in

GO:0060271: cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-120327-3

P

Seeded From UniProt

complete

Notes

See also

References

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