Complement Component C3 Is Highly Expressed in Human Pancreatic Islets and Prevents β Cell Death via ATG16L1 Interaction and Autophagy Regulation

Highlights

• Islet C3 expression is upregulated in human T2D and rodent models of diabetes

• C3 is present within the cytosol and binds autophagy-related protein 16-1 (ATG16L1)

• β cells lacking C3 have impaired autophagy

• Intracellular C3 protects β cells from palmitic acid/IAPP-mediated apoptosis

Summary

We show here that human pancreatic islets highly express C3, which is both secreted and present in the cytosol. Within isolated human islets, C3 expression correlates with type 2 diabetes (T2D) donor status, HbA1c, and inflammation. Islet C3 expression is also upregulated in several rodent diabetes models. C3 interacts with ATG16L1, which is essential for autophagy. Autophagy relieves cellular stresses faced by β cells during T2D and maintains cellular homeostasis. C3 knockout in clonal β cells impaired autophagy and led to increased apoptosis after exposure of cells to palmitic acid and IAPP. In the absence of C3, autophagosomes do not undergo fusion with lysosomes. Thus, C3 may be upregulated in islets during T2D as a cytoprotective factor against β cell dysfunction caused by impaired autophagy. Therefore, we revealed a previously undescribed intracellular function for C3, connecting the complement system directly to autophagy, with a broad potential importance in other diseases and cell types.