IPMK Mediates Activation of ULK Signaling and Transcriptional Regulation of Autophagy Linked to Liver Inflammation and Regeneration
IPMK Mediates Activation of ULK Signaling and Transcriptional Regulation of Autophagy Linked to Liver Inflammation and Regeneration
复制标题
DOI：
10.1016/j.celrep.2019.02.013
复制
发表时间：
2019-03-05
期刊：
影响因子：
8.8
通讯作者：
Snyder, Solomon H.
中科院分区：
文献类型：
--
作者：
Guha, Prasun;Tyagi, Richa;Snyder, Solomon H.
自噬在健康和疾病中发挥着广泛的作用。在这里，我们发现肌醇多磷酸多激酶（IPMK）是自噬的重要生理决定因素，对肝脏炎症和再生至关重要。IPMK的缺失减少了细胞系和小鼠肝脏的自噬。IPMK对自噬的调节不需要催化活性。两个信号轴IPMK- ampk - sirt -1和IPMK- ampk - ulk1似乎介导IPMK对自噬的影响。IPMK通过刺激ampk依赖的Sirt-1激活，介导组蛋白4赖氨酸16的去乙酰化，从而增强自噬相关的转录。此外，IPMK与ULK和AMPK直接结合形成三元复合物，促进AMPK依赖性ULK磷酸化。在细胞系和完整小鼠中，IPMK的缺失几乎可以消除脂噬，促进肝损伤和炎症，并损害肝细胞再生。因此，靶向IPMK可能为依赖自噬和脂噬的残疾提供治疗益处，特别是在肝脏炎症和再生中。
Autophagy plays a broad role in health and disease. Here, we show that inositol polyphosphate multikinase (IPMK) is a prominent physiological determinant of autophagy and is critical for liver inflammation and regeneration. Deletion of IPMK diminishes autophagy in cell lines and mouse liver. Regulation of autophagy by IPMK does not require catalytic activity. Two signaling axes, IPMK-AMPK-Sirt-1 and IPMK-AMPK-ULK1, appear to mediate the influence of IPMK on autophagy. IPMK enhances autophagy-related transcription by stimulating AMPK-dependent Sirt-1 activation, which mediates the deacetylation of histone 4 lysine 16. Furthermore, direct binding of IPMK to ULK and AMPK forms a ternary complex that facilitates AMPK-dependent ULK phosphorylation. Deletion of IPMK in cell lines and intact mice virtually abolishes lipophagy, promotes liver damage as well as inflammation, and impairs hepatocyte regeneration. Thus, targeting IPMK may afford therapeutic benefits in disabilities that depend on autophagy and lipophagy-specifically, in liver inflammation and regeneration.