Small ubiquitin-like modifier modification of arrestin-3 regulates receptor trafficking.
Nonvisual arrestins are regulated by direct post-translational modifications, such as phosphorylation, ubiquitination, and nitrosylation. However, whether arrestins are regulated by other post-translational modifications remains unknown. Here we show that nonvisual arrestins are modified by small ubiquitin-like modifier 1 (SUMO-1) upon activation of β(2)-adrenergic receptor (β(2)AR). Lysine residues 295 and 400 in arrestin-3 fall within canonical SUMO consensus sites, and mutagenic analysis reveals that Lys-400 represents the main SUMOylation site. Depletion of the SUMO E2 modifying enzyme Ubc9 blocks arrestin-3 SUMOylation and attenuates β(2)AR internalization, suggesting that arrestin SUMOylation mediates G protein-coupled receptor endocytosis. Consistent with this, expression of a SUMO-deficient arrestin mutant failed to promote β(2)AR internalization as compared with wild-type arrestin-3. Our data reveal an unprecedented role for SUMOylation in mediating GPCR endocytosis and provide novel mechanistic insight into arrestin function and regulation.
Department of Pharmacology, School of Medicine, Loyola University Chicago, Maywood, Illinois 60153, USA.
Debra
D
Wyatt
Rohit
R
Malik
Alissa C
AC
Vesecky
Adriano
A
Marchese
D000818:Animals; D019390:Arrestins / Q000378:metabolism* / Q000502:physiology; D001665:Binding Sites; D002417:Cattle; D002460:Cell Line; D004705:Endocytosis; D006801:Humans; D011499:Protein Processing, Post-Translational; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000378:metabolism; D058207:Sumoylation / Q000502:physiology*
D019390:Arrestins; D018343:Receptors, Adrenergic, beta-2; D043562:Receptors, G-Protein-Coupled; D025842:SUMO-1 Protein; C082333:arrestin3