title: Glia Maturation Factor-γ Regulates Monocyte Migration through Modulation of β1-Integrin.
abstract: Monocyte migration requires the dynamic redistribution of integrins through a regulated endo-exocytosis cycle, but the complex molecular mechanisms underlying this process have not been fully elucidated. Glia maturation factor-γ (GMFG), a novel regulator of the Arp2/3 complex, has been shown to regulate directional migration of neutrophils and T-lymphocytes. In this study, we explored the important role of GMFG in monocyte chemotaxis, adhesion, and β1-integrin turnover. We found that knockdown of GMFG in monocytes resulted in impaired chemotactic migration toward formyl-Met-Leu-Phe (fMLP) and stromal cell-derived factor 1α (SDF-1α) as well as decreased α5β1-integrin-mediated chemoattractant-stimulated adhesion. These GMFG knockdown impaired effects could be reversed by cotransfection of GFP-tagged full-length GMFG. GMFG knockdown cells reduced the cell surface and total protein levels of α5β1-integrin and increased its degradation. Importantly, we demonstrate that GMFG mediates the ubiquitination of β1-integrin through knockdown or overexpression of GMFG. Moreover, GMFG knockdown retarded the efficient recycling of β1-integrin back to the plasma membrane following normal endocytosis of α5β1-integrin, suggesting that the involvement of GMFG in maintaining α5β1-integrin stability may occur in part by preventing ubiquitin-mediated degradation and promoting β1-integrin recycling. Furthermore, we observed that GMFG interacted with syntaxin 4 (STX4) and syntaxin-binding protein 4 (STXBP4); however, only knockdown of STXBP4, but not STX4, reduced monocyte migration and decreased β1-integrin cell surface expression. Knockdown of STXBP4 also substantially inhibited β1-integrin recycling in human monocytes. These results indicate that the effects of GMFG on monocyte migration and adhesion probably occur through preventing ubiquitin-mediated proteasome degradation of α5β1-integrin and facilitating effective β1-integrin recycling back to the plasma membrane.
authors.affiliation: From the Molecular and Clinical Hematology Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892 and.
authors.forename: Wulin
authors.initials: W
authors.lastname: Aerbajinai
authors.affiliation: the Laboratory of Cellular and Molecular Biology, NCI, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Lunhua
authors.initials: L
authors.lastname: Liu
authors.affiliation: From the Molecular and Clinical Hematology Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892 and.
authors.forename: Jianqiong
authors.initials: J
authors.lastname: Zhu
authors.affiliation: From the Molecular and Clinical Hematology Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892 and.
authors.forename: Chutima
authors.initials: C
authors.lastname: Kumkhaek
authors.affiliation: From the Molecular and Clinical Hematology Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892 and.
authors.forename: Kyung
authors.initials: K
authors.lastname: Chin
authors.affiliation: From the Molecular and Clinical Hematology Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892 and gr5n@nih.gov.
authors.forename: Griffin P
authors.initials: GP
authors.lastname: Rodgers
mesh_terms: D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D054377:Chemokine CXCL12 / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D020904:Glia Maturation Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D039081:Integrin alpha5beta1 / Q000235:genetics / Q000378:metabolism; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D050765:Qa-SNARE Proteins / Q000235:genetics / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D020904:Glia Maturation Factor; D039081:Integrin alpha5beta1; D019012:Integrin beta1; D050765:Qa-SNARE Proteins; C498469:STXBP4 protein, human; D033921:Vesicular Transport Proteins; C587292:syntaxin 4, human; D009240:N-Formylmethionine Leucyl-Phenylalanine
keywords: Arp2/3 complex; adhesion; cell migration; endocytosis; glia maturation factor-gamma (GMFG); integrin; ubiquitylation (ubiquitination)