ABSTRACT

Hormone synthesis and secretion is a highly regulated process governed by metabolic cues. Although peptide hormone action is largely governed by the rate of its synthesis and secretion by endocrine cells, and the levels of its receptors on the target cells, intracellular degradation of the hormone-containing secretory vesicles by lysosomes (crinophagy) adds an additional layer of regulation. In our recent study, we uncovered the regulatory mechanism governing the crinophagic turnover of GCG (glucagon), a glycoprotein hormone secreted by pancreatic α-cells. Our results showed that inhibition of MTORC1 induces crinophagy-mediated degradation of glucagon and decreases its secretion in response to hypoglycemia. Furthermore, we demonstrated that crinophagy-regulated glucagon turnover does not involve macroautophagy. These results suggest that modulation of crinophagy may serve as a novel therapeutic strategy to regulate hormone secretion in endocrine and metabolic pathologies.

摘要

激素合成和分泌是由代谢线索控制的高度调节的过程。尽管肽激素的作用在很大程度上受内分泌细胞合成和分泌的速率以及靶细胞上受体水平的控制，但溶酶体对含有激素的分泌囊泡的细胞内降解（crinophagy）增加了一层额外的调节. 在我们最近的研究中，我们揭示了控制 GCG（胰高血糖素）的吞噬周转的调节机制，GCG 是一种由胰腺 α 细胞分泌的糖蛋白激素。我们的研究结果表明，抑制 MTORC1 会诱导 crinophagy 介导的胰高血糖素降解，并降低其分泌以应对低血糖。此外，我们证明了 crinophagy 调节的胰高血糖素转换不涉及巨自噬。