Structural and functional impairment of endocytic pathways by retinitis pigmentosa mutant rhodopsin-arrestin complexes
Jen-Zen Chuang, Carrie Vega, Wenjin Jun, Ching-Hwa Sung
Jen-Zen Chuang, Carrie Vega, Wenjin Jun, Ching-Hwa Sung
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Article Neuroscience

Structural and functional impairment of endocytic pathways by retinitis pigmentosa mutant rhodopsin-arrestin complexes

Abstract

Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous degenerative eye disease. Mutations at Arg135 of rhodopsin are associated with a severe form of autosomal dominant RP. This report presents evidence that Arg135 mutant rhodopsins (e.g., R135L, R135G, and R135W) are hyperphosphorylated and bind with high affinity to visual arrestin. Mutant rhodopsin recruits the cytosolic arrestin to the plasma membrane, and the rhodopsin-arrestin complex is internalized into the endocytic pathway. Furthermore, the rhodopsin-arrestin complexes alter the morphology of endosomal compartments and severely damage receptor-mediated endocytic functions. The biochemical and cellular defects of Arg135 mutant rhodopsins are distinct from those previously described for class I and class II RP mutations, and, hence, we propose that they be named class III. Impaired endocytic activity may underlie the pathogenesis of RP caused by class III rhodopsin mutations.

Authors

Jen-Zen Chuang, Carrie Vega, Wenjin Jun, Ching-Hwa Sung

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Figure 5

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Aberrant endosomal organization caused by R135L/GFPv-arr. Fixed, transfe...
Aberrant endosomal organization caused by R135L/GFPv-arr. Fixed, transfected cells were incubated with mAb’s that recognized early endosome marker EEA1 (A and B), early/recycling endosome marker TfR (C and D), and late endosome/lysosome marker lysosomal-associated membrane protein 1 (LAMP1) (E and F), followed by Alexa 594–conjugated anti-mouse Ab. GFP signals were used to directly visualize the GFPv-arr. The transfected cells are encircled in B, D, and F to show the cell margins. Although EEA1, TfR, and LAMP1 signals were dispersed in nontransfected cells, their signals were predominantly concentrated in the GFP+ perinuclear structures in the R135L/GFPv-arr–transfected cells. Scale bars: 10 μm.