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
Section of Microbial Pathogenesis, Boyer Center for Molecular Medicine, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06510, USA.
J Cell Biol. 2003 Aug 18;162(4):543-9. 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.
突触结合蛋白家族的成员被认为在膜融合中作为钙离子传感器发挥作用。突触结合蛋白VII是一种广泛表达的突触结合蛋白，先前已被证明与质膜修复和克氏锥虫入侵有关，这些事件是由钙离子调节的溶酶体胞吐作用介导的。在这里，我们表明，来自缺乏突触结合蛋白VII的小鼠的胚胎成纤维细胞对锥虫入侵的敏感性较低，并且在溶酶体胞吐作用和受伤后的重新封闭方面存在缺陷。对突变小鼠组织的检查显示，皮肤和骨骼肌出现广泛纤维化。炎症性肌病伴有白细胞侵入肌纤维和肌内膜胶原沉积，与肌酸激酶释放升高和进行性肌无力有关。有趣的是，与人类多发性肌炎/皮肌炎中观察到的情况类似，这些小鼠产生了强烈的抗核抗体反应，这是自身免疫性疾病的特征。因此，在机械应力下组织中的质膜修复缺陷可能有利于炎症性自身免疫疾病的发展。
