Impaired Membrane Resealing and Autoimmune Myositis in Synaptotagmin VII-Deficient Mice

• Published in: The Journal of cell biology Vol. 162; no. 4; pp. 543 - 549
• Main Authors: Chakrabarti, Sabyasachi, Kobayashi, Koichi S., Flavell, Richard A., Marks, Carolyn B., Miyake, Katsuya, Liston, David R., Fowler, Kimberly T., Gorelick, Fred S., Andrews, Norma W.
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 18.08.2003; The Rockefeller University Press
• Subjects: Animals; Antibodies; Calcium; Calcium - metabolism; Calcium-Binding Proteins; Cell Membrane - metabolism; Cell membranes; Cellular biology; Collagens; Dermatomyositis - pathology; Disease Models, Animal; Epithelial cells; Exocytosis; Immune system; Leukocytes; Lysosomes; Membrane Glycoproteins - deficiency; Membrane Glycoproteins - genetics; Mice; Mice, Knockout; Muscle, Skeletal - immunology; Muscle, Skeletal - pathology; Nerve Tissue Proteins - deficiency; Nerve Tissue Proteins - genetics; Polymyositis - pathology; Rodents; Skeletal muscle; Skin - immunology; Skin - pathology; Synaptotagmins; T lymphocytes
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.200305131

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.