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Impaired membrane resealing and autoimmune myositis in synaptotagmin VII-deficient mice
Sabyasachi Chakrabarti1, Koichi S Kobayashi, Richard A Flavell
1Section of Microbial Pathogenesis, Boyer Center for Molecular Medicine, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06510, USA.
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.
Insights
Synaptotagmin VII (Syt VII) deficiency impairs plasma membrane repair and lysosomal exocytosis. This defect in Syt VII-deficient mice leads to tissue damage and autoimmune disease, similar to human polymyositis.
Area of Science:
- Cell Biology
- Immunology
- Molecular Biology
Background:
- Synaptotagmins are calcium sensors involved in membrane fusion.
- Synaptotagmin VII (Syt VII) is implicated in plasma membrane repair and pathogen invasion.
- Lysosomal exocytosis is crucial for these processes.
Purpose of the Study:
- To investigate the role of Syt VII in plasma membrane repair and its physiological consequences.
- To determine the impact of Syt VII deficiency on lysosomal exocytosis and tissue integrity.
- To explore the potential link between Syt VII function and autoimmune disorders.
Main Methods:
- Utilized Syt VII-deficient mouse embryonic fibroblasts.
- Assessed trypanosome invasion, lysosomal exocytosis, and membrane resealing after wounding.
- Examined tissues from mutant mice for fibrosis, inflammation, and immune markers.
- Measured creatine kinase levels and assessed muscle function.
Main Results:
- Syt VII-deficient fibroblasts showed reduced trypanosome invasion and impaired lysosomal exocytosis and resealing.
- Mutant mice exhibited skin and skeletal muscle fibrosis.
- Mice developed inflammatory myopathy, leukocyte invasion, collagen deposition, and progressive muscle weakness.
- Syt VII-deficient mice produced antinuclear antibodies, indicating an autoimmune response.
Conclusions:
- Syt VII is essential for efficient plasma membrane repair and lysosomal exocytosis.
- Defective membrane repair in Syt VII-deficient mice leads to tissue damage and autoimmune disease.
- Impaired plasma membrane repair under mechanical stress may trigger inflammatory autoimmune conditions.
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