Complement Component C3 Is Highly Expressed in Human Pancreatic Islets and Prevents β Cell Death via ATG16L1 Interaction and Autophagy Regulation
Complement Component C3 Is Highly Expressed in Human Pancreatic Islets and Prevents β Cell Death via ATG16L1 Interaction and Autophagy Regulation
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DOI：
10.1016/j.cmet.2018.09.009
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发表时间：
2019-01-08
期刊：
影响因子：
29
通讯作者：
Blom, Anna M.
中科院分区：
文献类型：
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作者：
King, Ben C.;Kulak, Klaudia;Blom, Anna M.
我们在这里表明，人类胰岛高度表达C3，这是分泌和存在于胞质溶胶。在分离的人类胰岛内，C3表达与2型糖尿病（T2D）供体状态、HbA1c和炎症相关。在几种啮齿类动物糖尿病模型中，胰岛C3表达也上调。C3与ATG16L1相互作用，这是自噬所必需的。自噬缓解T2D期间β细胞面临的细胞应激并维持细胞稳态。克隆B细胞中的C3敲除损害了自噬，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，自噬体不与溶酶体融合。因此，C3可能在T2D期间在胰岛中上调，作为针对由受损的自噬引起的B细胞功能障碍的细胞保护因子。因此，我们揭示了C3以前未描述的细胞内功能，将补体系统直接连接到自噬，在其他疾病和细胞类型中具有广泛的潜在重要性。
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 beta cells during T2D and maintains cellular homeostasis. C3 knockout in clonal b 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 b 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.