title: Rapid degeneration of rod photoreceptors expressing self-association-deficient arrestin-1 mutant.
abstract: 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.
authors.affiliation: Vanderbilt University, Nashville, TN 37232, United States.
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Song
authors.forename: Jungwon
authors.initials: J
authors.lastname: Seo
authors.forename: Faiza
authors.initials: F
authors.lastname: Baameur
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Vishnivetskiy
authors.forename: Qiuyan
authors.initials: Q
authors.lastname: Chen
authors.forename: Seunghyi
authors.initials: S
authors.lastname: Kook
authors.forename: Miyeon
authors.initials: M
authors.lastname: Kim
authors.forename: Evan K
authors.initials: EK
authors.lastname: Brooks
authors.forename: Christian
authors.initials: C
authors.lastname: Altenbach
authors.forename: Yuan
authors.initials: Y
authors.lastname: Hong
authors.forename: Susan M
authors.initials: SM
authors.lastname: Hanson
authors.forename: Maria C
authors.initials: MC
authors.lastname: Palazzo
authors.forename: Jeannie
authors.initials: J
authors.lastname: Chen
authors.forename: Wayne L
authors.initials: WL
authors.lastname: Hubbell
authors.forename: Eugenia V
authors.initials: EV
authors.lastname: Gurevich
authors.forename: Vsevolod V
authors.initials: VV
authors.lastname: Gurevich
mesh_terms: D000818:Animals; D019393:Arrestin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D016923:Cell Death; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D009154:Mutation; D055503:Protein Multimerization; D017948:Retinal Rod Photoreceptor Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D012243:Rhodopsin / Q000378:metabolism
chemical_list: D019393:Arrestin; D012243:Rhodopsin; D048670:MAP Kinase Kinase 4
keywords: Arrestin; Cell death; G protein-coupled receptor; G protein-coupled receptor kinase; GPCR; GRK; Monomer; P-Ops; P-Rh; P-Rh*; Retina; Rh; Rh*; Rhodopsin; Self-association; WT; dark phosphorylated rhodopsin; dark unphosphorylated rhodopsin; light-activated phosphorylated rhodopsin; light-activated unphosphorylated rhodopsin; phospho-opsin; wild type