title: Identification of a nuclear localization sequence in β-arrestin-1 and its functional implications.
abstract: A mounting body of evidence suggests that β-arrestin-1 plays important roles in the nucleus, but how β-arrestin-1 enters the nucleus remains unclear because no nuclear import signal has been identified in the β-arrestins. We sought to characterize the cellular localization of wild type β-arrestin-1 and a series of N domain mutants to determine the structural basis and functional implications of β-arrestin-1 nuclear localization. A seven-residue candidate nuclear localization sequence (NLS) was identified based on sequence analysis. Mutation of the NLS led to a loss of β-arrestin-1 nuclear localization in transfected cells. Exogenous expression of wild type β-arrestin-1 enhanced the transcriptional activity of nuclear factor κB (NF-κB) induced by bradykinin, whereas mutation of the NLS reduced this effect by two-thirds relative to wild type controls. Loss of β-arrestin-1 nuclear localization was accompanied by reduced recruitment of the CREB-binding protein and altered post-translational modification profile of p65/RelA. Further mutational analysis identified Lys(157) within the putative NLS as being critical to nuclear localization of β-arrestin-1. Substitution of Lys(157) to Ala led to reduced nuclear localization, decreased promoter binding by p65/RelA and decreased IL-1β gene transcription. These results demonstrate a critical role for β-arrestin-1 nuclear localization in scaffolding and transcriptional regulation.
authors.affiliation: Department of Pharmacology, College of Medicine, University of Illinois, Chicago, Illinois 60612, USA.
authors.forename: Crystal Zoe
authors.initials: CZ
authors.lastname: Hoeppner
authors.forename: Ni
authors.initials: N
authors.lastname: Cheng
authors.forename: Richard D
authors.initials: RD
authors.lastname: Ye
mesh_terms: D000595:Amino Acid Sequence; D019390:Arrestins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D019913:Nuclear Localization Signals; D021381:Protein Transport; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
chemical_list: C000605253:ARRB1 protein, human; D019390:Arrestins; D019913:Nuclear Localization Signals; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins