Abstract
Calpain-10 (CAPN10) is the calpain family protease identified as the first candidate susceptibility gene for type 2 diabetes mellitus (T2DM). However, the detailed molecular mechanism has not yet been elucidated. Here we report that CAPN10 processes microtubule associated protein 1 (MAP1) family proteins into heavy and light chains and regulates their binding activities to microtubules and actin filaments. Immunofluorescent analysis of Capn10−/− mouse embryonic fibroblasts shows that MAP1B, a member of the MAP1 family of proteins, is localized at actin filaments rather than at microtubules. Furthermore, fluorescence recovery after photo-bleaching analysis shows that calpain-10 regulates actin dynamics via MAP1B cleavage. Moreover, in pancreatic islets from CAPN10 knockout mice, insulin secretion was significantly increased both at the high and low glucose levels. These findings indicate that deficiency of calpain-10 expression may affect insulin secretion by abnormal actin reorganization, coordination and dynamics through MAP1 family processing.
Highlights
Calpains are a family of intracellular non-lysosomal calcium-activated neutral cysteine proteases known to cleave various substrate proteins and modulate their activities
Our findings show that CAPN10 is required in processing microtubule-associated protein 1 (MAP1) family proteins and regulation of their binding activities to microtubules and actin, both of which could readily affect insulin secretion and action through impaired actin reorganization, coordination and dynamics
The findings suggest that CAPN10 is an microtubule-associated protein 1B (MAP1B) processing enzyme necessary for the mature heavy chain (HC)/light chain (LC) complex formation required for localization to microtubules (Fig. S7)
Summary
Calpains are a family of intracellular non-lysosomal calcium-activated neutral cysteine proteases known to cleave various substrate proteins and modulate their activities. Reduced CAPN10 expression has been found to decrease insulin-stimulated GLUT4 vesicle translocation, actin reorganization and glucose uptake in adipocytes[3]. It was reported that targeted suppression of CAPN10 expression impairs insulin-stimulated glucose uptake in skeletal muscle[4]. Previous reports show that CAPN10 is implicated in insulin secretion and action and facilitates actin reorganization during glucose-stimulated insulin secretion and insulin-stimulated glucose uptake. Since CAPN10 is expressed in various tissues, target substrates of the protein and other related factors could act together in development of diabetes. Our findings show that CAPN10 is required in processing MAP1 family proteins and regulation of their binding activities to microtubules and actin, both of which could readily affect insulin secretion and action through impaired actin reorganization, coordination and dynamics
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