Impaired membrane resealing and autoimmune myositis in synaptotagmin VII-deficient mice

doi:10.1083/jcb.200305131

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Published 18 August 2003. doi:10.1083/jcb.200305131

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© The Rockefeller University Press, 0021-9525/2003/8/543 $5.00
The Journal of Cell Biology, Volume 162, Number 4, 543-549

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Impaired membrane resealing and autoimmune myositis in synaptotagmin VII–deficient mice

Sabyasachi Chakrabarti¹, Koichi S. Kobayashi², Richard A. Flavell², Carolyn B. Marks³^,4, Katsuya Miyake⁶, David R. Liston¹^,3, Kimberly T. Fowler¹^,3, Fred S. Gorelick³^,5 and Norma W. Andrews¹^,3

¹ Section of Microbial Pathogenesis, Boyer Center for Molecular Medicine
² Section of Immunobiology, Howard Hughes Medical Institute
³ Department of Cell Biology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510
⁴ Center for Cell and Molecular Imaging, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510
⁵ Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510
⁶ Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA 30912

Address correspondence to Norma W. Andrews, Section of Microbial Pathogenesis, Boyer Center for Molecular Medicine, Yale University School of Medicine, 295 Congress Ave., New Haven, CT 06510. Tel.: (203) 737-2410. Fax: (203) 737-2630. email: norma.andrews{at}yale.edu

Members of the synaptotagmin family have been proposed to functionas Ca²⁺ sensors in membrane fusion. Syt VII is a ubiquitouslyexpressed synaptotagmin previously implicated in plasma membranerepair and Trypanosoma cruzi invasion, events which are mediatedby the Ca²⁺-regulated exocytosis of lysosomes. Here, we showthat embryonic fibroblasts from Syt VII–deficient miceare less susceptible to trypanosome invasion, and defectivein lysosomal exocytosis and resealing after wounding. Examinationof mutant mouse tissues revealed extensive fibrosis in the skinand skeletal muscle. Inflammatory myopathy, with muscle fiberinvasion by leukocytes and endomysial collagen deposition, wasassociated with elevated creatine kinase release and progressivemuscle weakness. Interestingly, similar to what is observedin human polymyositis/dermatomyositis, the mice developed astrong antinuclear antibody response, characteristic of autoimmunedisorders. Thus, defective plasma membrane repair in tissuesunder mechanical stress may favor the development of inflammatoryautoimmune disease.

Key Words: exocytosis; repair; lysosome; inflammatory myopathy; knockout mouse

Abbreviations used in this paper: DMEM, Dulbecco's minimal essentialmedium; ES, embryonic stem; LDH, lactate dehydrogenase; MEF,murine embryonic fibroblast.

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