Section of Medical Protein Chemistry, Department of Translational Medicine, Lund University, 214-28 Malmö, Sweden.
Lund University Diabetes Centre, Department of Clinical Sciences Malmö, Lund University, 214-28 Malmö, Sweden.
Cell Metab. 2019 Jan 8;29(1):202-210.e6. doi: 10.1016/j.cmet.2018.09.009. Epub 2018 Oct 4.
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.
我们在这里表明，人类胰岛高度表达 C3，C3 既被分泌出来，也存在于细胞质中。在分离的人类胰岛中，C3 的表达与 2 型糖尿病 (T2D) 供体状态、HbA1c 和炎症相关。几种啮齿动物糖尿病模型中胰岛 C3 的表达也上调。C3 与 ATG16L1 相互作用，ATG16L1 对自噬至关重要。自噬缓解了 T2D 期间 β 细胞面临的细胞应激，并维持了细胞内稳态。在克隆的 β 细胞中敲除 C3 会损害自噬，并导致细胞暴露于棕榈酸和 IAPP 后凋亡增加。在没有 C3 的情况下，自噬体不会与溶酶体融合。因此，C3 可能在 T2D 期间作为一种细胞保护因子在胰岛中上调，以防止自噬受损引起的 β 细胞功能障碍。因此，我们揭示了 C3 的一个以前未描述的细胞内功能，将补体系统直接与自噬联系起来，这在其他疾病和细胞类型中具有广泛的潜在重要性。
