Abstract
SUMMARYAutophagy 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-depen-dent 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.
Highlights
Autophagy occurs at a basal rate in most cells, eliminating protein aggregates and damaged organelles to maintain cytoplasmic homeostasis
Inositol polyphosphates are major signaling molecules generated by a family of inositol phosphate kinases that successively phosphorylate the inositol ring, leading to the formation of inositol polyphosphate multikinase (IPMK) Is Essential for Autophagy To investigate the roles of IPMK in autophagy, we generated immortalized IPMK wild-type (WT)/knockout (KO) MEFs (Maag et al, 2011)
To ensure that the findings with glucose starvation can be generalized to other autophagic stimuli, we evaluated H2O2 treatment, which is well-known to elicit autophagy (He et al, 2017)
Summary
Guha et al show that IPMK is a physiological determinant of autophagy and is critical in liver inflammation. IPMK-AMPK-Sirt-1 and IPMK-AMPK- ULK1, appear to mediate the influence of IPMK on autophagy. Deletion of IPMK impairs lipophagy and hepatocyte regeneration. 2019, Cell Reports 26, 2692–2703 March 5, 2019 a 2019 The Author(s).
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