title: Proteomic analysis reveals a FANCA-modulated neddylation pathway involved in CXCR5 membrane targeting and cell mobility.
abstract: The aim of this study was to identify novel substrates of the FANCcore complex, the inactivation of which leads to the genetic disorder Fanconi anemia, which is associated with bone marrow failure, developmental abnormalities and a predisposition to cancer. Eight FANC proteins participate in the nuclear FANCcore complex, which functions as an E3 ubiquitin-ligase that monoubiquitylates FANCD2 and FANCI in response to replicative stress. Here, we use mass spectrometry to compare proteins from FANCcore-complex-deficient cells to those of rescued control cells after treatment with hydroxyurea, an inducer of FANCD2 monoubiquitylation. FANCD2 and FANCI appear to be the only targets of the FANCcore complex. We identify other proteins that are post-translationally modified in a FANCA- or FANCC-dependent manner. The majority of these potential targets localize to the cell membrane. Finally, we demonstrate that (a) the chemokine receptor CXCR5 is neddylated; (b) FANCA but not FANCC appears to modulate CXCR5 neddylation through an unknown mechanism; (c) CXCR5 neddylation is involved in targeting the receptor to the cell membrane; and (d) CXCR5 neddylation stimulates cell migration and motility. Our work has uncovered a pathway involving FANCA in neddylation and cell motility.
authors.affiliation: Université Paris-Sud, 91400 Orsay, France CNRS UMR 8200 - Institut de Cancérologie Gustave Roussy, 94805 Villejuif, France Equipe Labellisée Ligue Contre le Cancer, 14 Rue Corvisart, 75013 Paris.
authors.forename: Xavier
authors.initials: X
authors.lastname: Renaudin
authors.affiliation: Université Paris-Sud, 91400 Orsay, France CNRS UMR 8200 - Institut de Cancérologie Gustave Roussy, 94805 Villejuif, France Equipe Labellisée Ligue Contre le Cancer, 14 Rue Corvisart, 75013 Paris.
authors.forename: Jean-Hugues
authors.initials: JH
authors.lastname: Guervilly
authors.affiliation: Université Paris-Sud, 91400 Orsay, France CNRS UMR 8200 - Institut de Cancérologie Gustave Roussy, 94805 Villejuif, France.
authors.forename: Said
authors.initials: S
authors.lastname: Aoufouchi
authors.affiliation: Université Paris-Sud, 91400 Orsay, France CNRS UMR 8200 - Institut de Cancérologie Gustave Roussy, 94805 Villejuif, France Equipe Labellisée Ligue Contre le Cancer, 14 Rue Corvisart, 75013 Paris filippo.rosselli@gustaveroussy.fr.
authors.forename: Filippo
authors.initials: F
authors.lastname: Rosselli
mesh_terms: D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D052217:Fanconi Anemia Complementation Group A Protein / Q000235:genetics / Q000378:metabolism; D052218:Fanconi Anemia Complementation Group C Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000075687:NEDD8 Protein; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D040901:Proteomics; D054380:Receptors, CXCR5 / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism
chemical_list: C095085:CXCR5 protein, human; C498471:FANCA protein, human; D052217:Fanconi Anemia Complementation Group A Protein; D052218:Fanconi Anemia Complementation Group C Protein; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D054380:Receptors, CXCR5; D014452:Ubiquitins
keywords: CXCR5; Cell motility; Fanconi anemia; Leukemia; NEDD8