Intracellular cytosolic complement component C3 regulates cytoprotective autophagy in pancreatic beta cells by...

Complement component C3 is central to the complement system, a humoral effector mechanism of innate immune defense. When activated, C3 covalently binds to target particles, marking them for uptake and clearance by phagocytosis. We now show that C3 also exists within the cytosol where it interacts with ATG16L1, and is therefore involved in the intracellular clearance and recycling of material by macroautophagy/autophagy in pancreatic beta cells. C3 is highly expressed in isolated human islets, and its expression is upregulated in islets isolated from diabetic patients and rodents, and correlates with patient HBA1c and body mass index (BMI). Knockout of C3 in clonal beta cells leads to dysfunctional autophagy, and increased cell death after challenge with diabetogenic stresses, which are usually alleviated by increased autophagic turnover. However, autophagic degradation of INS (insulin) granules regulates total INS content, and increased autophagy due to C3 upregulation may deplete beta cell INS stores. C3 is therefore required for efficient autophagic turnover in beta cells, and is upregulated as a cytoprotective factor during diabetes.