title: Impaired membrane resealing and autoimmune myositis in synaptotagmin VII-deficient mice.
abstract: Members of the synaptotagmin family have been proposed to function as Ca2+ sensors in membrane fusion. Syt VII is a ubiquitously expressed synaptotagmin previously implicated in plasma membrane repair and Trypanosoma cruzi invasion, events which are mediated by the Ca2+-regulated exocytosis of lysosomes. Here, we show that embryonic fibroblasts from Syt VII-deficient mice are less susceptible to trypanosome invasion, and defective in lysosomal exocytosis and resealing after wounding. Examination of mutant mouse tissues revealed extensive fibrosis in the skin and skeletal muscle. Inflammatory myopathy, with muscle fiber invasion by leukocytes and endomysial collagen deposition, was associated with elevated creatine kinase release and progressive muscle weakness. Interestingly, similar to what is observed in human polymyositis/dermatomyositis, the mice developed a strong antinuclear antibody response, characteristic of autoimmune disorders. Thus, defective plasma membrane repair in tissues under mechanical stress may favor the development of inflammatory autoimmune disease.
authors.affiliation: Section of Microbial Pathogenesis, Boyer Center for Molecular Medicine, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06510, USA.
authors.forename: Sabyasachi
authors.initials: S
authors.lastname: Chakrabarti
authors.forename: Koichi S
authors.initials: KS
authors.lastname: Kobayashi
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Carolyn B
authors.initials: CB
authors.lastname: Marks
authors.forename: Katsuya
authors.initials: K
authors.lastname: Miyake
authors.forename: David R
authors.initials: DR
authors.lastname: Liston
authors.forename: Kimberly T
authors.initials: KT
authors.lastname: Fowler
authors.forename: Fred S
authors.initials: FS
authors.lastname: Gorelick
authors.forename: Norma W
authors.initials: NW
authors.lastname: Andrews
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins; D002462:Cell Membrane / Q000378:metabolism*; D003882:Dermatomyositis / Q000473:pathology*; D004195:Disease Models, Animal; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000276:immunology / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics; D017285:Polymyositis / Q000473:pathology*; D012867:Skin / Q000276:immunology / Q000473:pathology; D050857:Synaptotagmins
chemical_list: D002135:Calcium-Binding Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C494303:Syt7 protein, mouse; D050857:Synaptotagmins; D002118:Calcium