Rapid degeneration of rod photoreceptors expressing self-association-deficient arrestin-1 mutant

• Published in: Cellular signalling Vol. 25; no. 12; pp. 2613 - 2624
• Main Authors: Song, Xiufeng, Seo, Jungwon, Baameur, Faiza, Vishnivetskiy, Sergey A., Chen, Qiuyan, Kook, Seunghyi, Kim, Miyeon, Brooks, Evan K., Altenbach, Christian, Hong, Yuan, Hanson, Susan M., Palazzo, Maria C., Chen, Jeannie, Hubbell, Wayne L., Gurevich, Eugenia V., Gurevich, Vsevolod V.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.12.2013
• Subjects: Animals; Arrestin; Arrestin - chemistry; Arrestin - genetics; Arrestin - metabolism; Cell Death; MAP Kinase Kinase 4 - metabolism; Mice; Monomer; Mutation; Protein Multimerization; Retina; Retinal Rod Photoreceptor Cells - cytology; Retinal Rod Photoreceptor Cells - metabolism; Retinal Rod Photoreceptor Cells - pathology; Rhodopsin; Rhodopsin - metabolism; Self-association; GRK; Rhodopsin; Self-association; Cell death; Rh; P-Rh; P-Ops; GPCR; Retina; Arrestin; Monomer; WT; G protein-coupled receptor; dark phosphorylated rhodopsin; G protein-coupled receptor kinase; light-activated unphosphorylated rhodopsin; wild type; phospho-opsin; dark unphosphorylated rhodopsin; light-activated phosphorylated rhodopsin
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2013.08.022

Arrestin-1 binds light-activated phosphorhodopsin and ensures timely signal shutoff. We show that high transgenic expression of an arrestin-1 mutant with enhanced rhodopsin binding and impaired oligomerization causes apoptotic rod death in mice. Dark rearing does not prevent mutant-induced cell death, ruling out the role of arrestin complexes with light-activated rhodopsin. Similar expression of WT arrestin-1 that robustly oligomerizes, which leads to only modest increase in the monomer concentration, does not affect rod survival. Moreover, WT arrestin-1 co-expressed with the mutant delays retinal degeneration. Thus, arrestin-1 mutant directly affects cell survival via binding partner(s) other than light-activated rhodopsin. Due to impaired self-association of the mutant its high expression dramatically increases the concentration of the monomer. The data suggest that monomeric arrestin-1 is cytotoxic and WT arrestin-1 protects rods by forming mixed oligomers with the mutant and/or competing with it for the binding to non-receptor partners. Thus, arrestin-1 self-association likely serves to keep low concentration of the toxic monomer. The reduction of the concentration of harmful monomer is an earlier unappreciated biological function of protein oligomerization. [Display omitted] •Monomeric arrestin-1 is cytotoxictoxic•Robust self-association of arestin-1 is a cytoprotective mechanism•Monomer toxicity might explain low expression of arrestin-4 in cones•Monomer toxicity might explain self-association of non-visual arrestins