title: The deubiquitinating enzyme USP17 is essential for GTPase subcellular localization and cell motility.
abstract: Deubiquitinating enzymes are now emerging as potential therapeutic targets that control many cellular processes, but few have been demonstrated to control cell motility. Here, we show that ubiquitin-specific protease 17 (USP17) is rapidly and transiently induced in response to chemokines SDF-1/CXCL12 and IL-8/CXCL8 in both primary cells and cell lines, and that its depletion completely blocks chemokine-induced cell migration and cytoskeletal rearrangements. Using live cell imaging, we demonstrate that USP17 is required for both elongated and amoeboid motility, in addition to chemotaxis. USP17 has previously been reported to disrupt Ras localization and we now find that USP17 depletion blocks chemokine-induced subcellular relocalization of GTPases Cdc42, Rac and RhoA, which are GTPases essential for cell motility. Collectively, these results demonstrate that USP17 has a critical role in cell migration and may be a useful drug target for both inflammatory and metastatic disease.
authors: Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University, Belfast BT9 7BL, Northern Ireland.
authors: Michelle
authors: M
authors: de la Vega
authors: Alyson A
authors: AA
authors: Kelvin
authors: Dara J
authors: DJ
authors: Dunican
authors: Cheryl
authors: C
authors: McFarlane
authors: James F
authors: JF
authors: Burrows
authors: Jakub
authors: J
authors: Jaworski
authors: Nigel J
authors: NJ
authors: Stevenson
authors: Karim
authors: K
authors: Dib
authors: Joshua Z
authors: JZ
authors: Rappoport
authors: Christopher J
authors: CJ
authors: Scott
authors: Aideen
authors: A
authors: Long
authors: James A
authors: JA
authors: Johnston
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D054377:Chemokine CXCL12 / Q000378:metabolism; D002633:Chemotaxis / Q000502:physiology; D003599:Cytoskeleton / Q000378:metabolism; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D021381:Protein Transport; D020741:rho GTP-Binding Proteins / Q000032:analysis / Q000378:metabolism*
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D016209:Interleukin-8; D010450:Endopeptidases; C484854:USP17L2 protein, human; D020741:rho GTP-Binding Proteins