ABSTRACT

A progressive decline in the macroautophagic/autophagic flux is a hallmark of pancreatic β-cell failure in type 2 diabetes (T2D) but the responsible intrinsic factors and underlying molecular mechanisms are incompletely understood. A stress-sensitive multicomponent cellular loop of the Hippo pathway kinase LATS2 (large tumor suppressor 2), MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) and autophagy regulates β-cell survival and metabolic adaptation. Chronic metabolic stress leads to LATS2 hyperactivation which then induces MTORC1, subsequently impairing the cellular autophagic flux and consequently triggering β-cell death. Reciprocally, under physiological conditions, autophagy controls β-cell survival by lysosomal degradation of LATS2. These signaling cross-talks and the interaction between autophagy and LATS2 are important for the regulation of β-cell turnover and functional compensation under metabolic stress.

摘要

巨自噬/自噬通量的逐渐下降是 2 型糖尿病 (T2D) 中胰腺 β 细胞衰竭的标志，但其相关的内在因素和潜在的分子机制尚不完全清楚。Hippo 通路激酶 LATS2（大肿瘤抑制因子 2）、MTOR（雷帕霉素激酶的机械靶点）复合物 1 (MTORC1) 和自噬的应激敏感多组分细胞环调节 β 细胞存活和代谢适应。慢性代谢应激导致 LATS2 过度活化，然后诱导 MTORC1，随后损害细胞自噬通量并因此引发 β 细胞死亡。反过来，在生理条件下，自噬通过 LATS2 的溶酶体降解来控制 β 细胞的存活。