Impaired membrane resealing and autoimmune myositis in synaptotagmin VII-deficient mice.
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.
Chakrabarti
Sabyasachi
S
Section of Microbial Pathogenesis, Boyer Center for Molecular Medicine, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06510, USA.
Kobayashi
Koichi S
KS
Flavell
Richard A
RA
Marks
Carolyn B
CB
Miyake
Katsuya
K
Liston
David R
DR
Fowler
Kimberly T
KT
Gorelick
Fred S
FS
Andrews
Norma W
NW
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
D002135:Calcium-Binding Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C494303:Syt7 protein, mouse; D050857:Synaptotagmins; D002118:Calcium