title: Autoinhibition regulates cellular localization and actin assembly activity of the diaphanous-related formins FRLalpha and mDia1.
abstract: Diaphanous-related formins (DRFs) are key regulators of actin cytoskeletal dynamics whose in vitro actin assembly activities are thought to be regulated by autoinhibition. However, the in vivo consequences of autoinhibition and the involvement of DRFs in specific biological processes are not well understood. In this study, we show that in the DRFs FRLalpha (formin-related gene in leukocytes alpha) and mouse diaphanous 1, autoinhibition regulates a novel membrane localization activity in vivo as well as actin assembly activity in vitro. In FRLalpha, the Rho family guanosine triphosphatase Cdc42 relieves the autoinhibition of both membrane localization and biochemical actin assembly activities. FRLalpha is required for efficient Fc-gamma receptor-mediated phagocytosis and is recruited to the phagocytic cup by Cdc42. These results suggest that mutual autoinhibition of biochemical activity and cellular localization may be a general regulatory principle for DRFs and demonstrate a novel role for formins in immune function.
authors.affiliation: Department of Biochemistry, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Seth
authors.forename: Chinatsu
authors.initials: C
authors.lastname: Otomo
authors.forename: Michael K
authors.initials: MK
authors.lastname: Rosen
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D025461:Feedback, Physiological; D000080865:Formins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D009154:Mutation; D010587:Phagocytosis; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D051381:Rats; D017452:Receptors, IgG / Q000378:metabolism; D014162:Transfection; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D002352:Carrier Proteins; C491464:Diap1 protein, mouse; C413382:Fmnl1 protein, mouse; D000080865:Formins; D047908:Intracellular Signaling Peptides and Proteins; D017452:Receptors, IgG; D020764:cdc42 GTP-Binding Protein