title: A functional interplay between the small GTPase Rab11a and mitochondria-shaping proteins regulates mitochondrial positioning and polarization of the actin cytoskeleton downstream of Src family kinases.
abstract: It is believed that mitochondrial dynamics is coordinated with endosomal traffic rates during cytoskeletal remodeling, but the mechanisms involved are largely unknown. The adenovirus early region 4 ORF4 protein (E4orf4) subverts signaling by Src family kinases (SFK) to perturb cellular morphology, membrane traffic, and organellar dynamics and to trigger cell death. Using E4orf4 as a model, we uncovered a functional connection between mitochondria-shaping proteins and the small GTPase Rab11a, a key regulator of polarized transport via recycling endosomes. We found that E4orf4 induced dramatic changes in the morphology of mitochondria along with their mobilization at the vicinity of a polarized actin network typifying E4orf4 action, in a manner controlled by SFK and Rab11a. Mitochondrial remodeling was associated with increased proximity between Rab11a and mitochondrial membranes, changes in fusion-fission dynamics, and mitochondrial relocalization of the fission factor dynamin-related protein 1 (Drp1), which was regulated by the Rab11a effector protein FIP1/RCP. Knockdown of FIP1/RCP or inhibition of Drp1 markedly impaired mitochondrial remodeling and actin assembly, involving Rab11a-mediated mitochondrial dynamics in E4orf4-induced signaling. A similar mobilization of mitochondria near actin-rich structures was mediated by Rab11 and Drp1 in viral Src-transformed cells and contributed to the biogenesis of podosome rosettes. These findings suggest a role for Rab11a in the trafficking of Drp1 to mitochondria upon SFK activation and unravel a novel functional interplay between Rab11a and mitochondria during reshaping of the cell cytoskeleton, which would facilitate mitochondria redistribution near energy-requiring actin-rich structures.
authors.affiliation: From the Centre de Recherche sur le Cancer de l'Université Laval, Centre de Recherche du Centre Hospitalier Universitaire de Québec, Axe Oncologie, Québec G1R 3S3 and.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Landry
authors.forename: Claudia
authors.initials: C
authors.lastname: Champagne
authors.forename: Marie-Chloé
authors.initials: MC
authors.lastname: Boulanger
authors.forename: Alexandra
authors.initials: A
authors.lastname: Jetté
authors.forename: Margit
authors.initials: M
authors.lastname: Fuchs
authors.forename: Claire
authors.initials: C
authors.lastname: Dziengelewski
authors.forename: Josée N
authors.initials: JN
authors.lastname: Lavoie
mesh_terms: D008841:Actin Cytoskeleton / Q000235:genetics / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*; D000099193:rab11 GTP-Binding Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D034281:Dynamins; D020558:GTP Phosphohydrolases; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D014764:Viral Proteins; D020691:rab GTP-Binding Proteins; D019061:src-Family Kinases; D000099193:rab11 GTP-Binding Proteins; C121517:E4orf4 protein, adenovirus; C488966:RAB11FIP1 protein, human; C110768:DNM1L protein, human
keywords: Ad E4orf4; Cytoskeleton; Drp1; Mitochondria; Podosome; Rab; Rab11-FIP; Src; Trafficking; Viral Protein