title: Dysferlin regulates cell adhesion in human monocytes.
abstract: Dysferlin is mutated in a group of muscular dystrophies commonly referred to as dysferlinopathies. It is highly expressed in skeletal muscle, where it is important for sarcolemmal maintenance. Recent studies show that dysferlin is also expressed in monocytes. Moreover, muscle of dysferlinopathy patients is characterized by massive immune cell infiltrates, and dysferlin-negative monocytes were shown to be more aggressive and phagocytose more particles. This suggests that dysferlin deregulation in monocytes might contribute to disease progression, but the molecular mechanism is unclear. Here we show that dysferlin expression is increased with differentiation in human monocytes and the THP1 monocyte cell model. Freshly isolated monocytes of dysferlinopathy patients show deregulated expression of fibronectin and fibronectin-binding integrins, which is recapitulated by transient knockdown of dysferlin in THP1 cells. Dysferlin forms a protein complex with these integrins at the cell membrane, and its depletion impairs cell adhesion. Moreover, patient macrophages show altered adhesion and motility. These findings suggest that dysferlin is involved in regulating cellular interactions and provide new insight into dysferlin function in inflammatory cells.
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors.forename: Antoine
authors.initials: A
authors.lastname: de Morrée
authors.affiliation: Servei de Neurologia, Laboratori de Neurologia Experimental, Hospital de la Santa Creu i Sant Pau i Institut de Recerca de HSCSP, Universitat Autònoma de Barcelona and Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 08193 Bellaterra, Spain.
authors.forename: Bàrbara
authors.initials: B
authors.lastname: Flix
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors.forename: Ivana
authors.initials: I
authors.lastname: Bagaric
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors.forename: Marlinde
authors.initials: M
authors.lastname: van den Boogaard
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors.forename: Laure
authors.initials: L
authors.lastname: Grand Moursel
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors.forename: Rune R
authors.initials: RR
authors.lastname: Frants
authors.affiliation: Servei de Neurologia, Laboratori de Neurologia Experimental, Hospital de la Santa Creu i Sant Pau i Institut de Recerca de HSCSP, Universitat Autònoma de Barcelona and Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 08193 Bellaterra, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Illa
authors.affiliation: Servei de Neurologia, Laboratori de Neurologia Experimental, Hospital de la Santa Creu i Sant Pau i Institut de Recerca de HSCSP, Universitat Autònoma de Barcelona and Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 08193 Bellaterra, Spain.
authors.forename: Eduard
authors.initials: E
authors.lastname: Gallardo
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors.forename: Rene
authors.initials: R
authors.lastname: Toes
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands. Electronic address: maarel@lumc.nl.
authors.forename: Silvère M
authors.initials: SM
authors.lastname: van der Maarel
mesh_terms: D002448:Cell Adhesion; D002454:Cell Differentiation; D000073939:Dysferlin; D005786:Gene Expression Regulation; D006801:Humans; D007107:Immune System; D007249:Inflammation; D039661:Integrin beta3 / Q000378:metabolism; D008264:Macrophages; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology*; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D009136:Muscular Dystrophies / Q000378:metabolism; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000378:metabolism; D009154:Mutation
chemical_list: C114839:DYSF protein, human; D000073939:Dysferlin; D039661:Integrin beta3; D008565:Membrane Proteins; D009124:Muscle Proteins
keywords: Cell Adhesion; Integrin; Monocytes; Muscular Dystrophy; Skeletal Muscle
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