Department of Molecular Genetics & Microbiology, Stony Brook University, Stony Brook, NY 11794, USA.
J Cell Biol. 2010 Nov 15;191(4):827-43. doi: 10.1083/jcb.201006056. Epub 2010 Nov 8.
Autophagy is an evolutionarily conserved cell renewal process that depends on phosphatidylinositol 3-phosphate (PtdIns(3)P). In metazoans, autophagy is inhibited by PtdIns(3,4,5)P(3), the product of class IA PI3Ks, which mediates the activation of the Akt-TOR kinase cascade. However, the precise function of class IA PI3Ks in autophagy remains undetermined. Class IA PI3Ks are heterodimeric proteins consisting of an 85-kD regulatory subunit and a 110-kD catalytic subunit. Here we show that the class IA p110-β catalytic subunit is a positive regulator of autophagy. Genetic deletion of p110-β results in impaired autophagy in mouse embryonic fibroblasts, liver, and heart. p110-β does not promote autophagy by affecting the Akt-TOR pathway. Rather, it associates with the autophagy-promoting Vps34-Vps15-Beclin 1-Atg14L complex and facilitates the generation of cellular PtdIns(3)P. Our results unveil a previously unknown function for p110-β as a positive regulator of autophagy in multicellular organisms.
自噬是一种进化上保守的细胞更新过程，依赖于磷脂酰肌醇 3-磷酸 (PtdIns(3)P)。在后生动物中，自噬被 PtdIns(3,4,5)P(3)抑制，PtdIns(3,4,5)P(3)是 I 类 PI3K 的产物，介导 Akt-TOR 激酶级联的激活。然而，I 类 PI3Ks 在自噬中的精确功能仍未确定。I 类 PI3Ks 是由 85kD 调节亚基和 110kD 催化亚基组成的异二聚体蛋白。在这里，我们表明 I 类 p110-β 催化亚基是自噬的正调节剂。p110-β 的基因缺失导致小鼠胚胎成纤维细胞、肝脏和心脏中的自噬受损。p110-β 不会通过影响 Akt-TOR 途径来促进自噬。相反，它与促进自噬的 Vps34-Vps15-Beclin 1-Atg14L 复合物结合，并促进细胞 PtdIns(3)P 的产生。我们的结果揭示了 p110-β 作为多细胞生物中自噬的正调节剂的先前未知功能。
