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Cited by 48Autophagy in Disease and TherapyLiver physiology and pathologyMetabolism, Diabetes, and Cancer

IPMK Mediates Activation of ULK Signaling and Transcriptional Regulation of Autophagy Linked to Liver Inflammation and Regeneration

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Guha, Prasun, Tyagi, Richa, Chowdhury, Sayan, Reilly, Luke, Fu, Chenglai, Xu, Risheng, Resnick, Adam C., Snyder, Solomon H.·2019·Cell Reports
DOI 10.1016/j.celrep.2019.02.013PMC PMC6494083
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Abstract

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.

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  • The reduction in InsP5 and InsP6 upon IPMK deletion is primarily attributed to the decrease in InsP5 levels, which serves as the major precursor of InsP6.

    “This reduction is primarily attributed to the decrease in InsP5 levels, which serves as the major precursor of InsP6 upon IPMK deletion, underscoring the critical role of IPMK in regulating HOIPs levels.”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [14]

    The Introduction says IPMK generates IP5 and describes successive phosphorylation leading to IP6. The Results mention inositol profiling, but the passages in our copy do not state that IPMK deletion reduces both levels or that the IP6 reduction is primarily caused by a fall in IP5. Page numbers are unavailable in our copy. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • IPMK acts as a rate-limiting enzyme in the HOIP pathway.

    “IPMK acts as a rate-limiting enzyme, with its loss of function significantly impacting the production of downstream HOIPs such as InsP4, InsP5, InsP6, InsP7, and InsP8 [13,14].”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [14]

    The Introduction (page unavailable) says IPMK generates IP4 and IP5 and describes a pathway leading to IP6, IP7, and IP8. It does not identify IPMK as rate-limiting or report that its loss significantly reduces production of all those downstream compounds. The Results’ inositol-profiling passage (page unavailable) describes a method, not that claimed effect. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Loss of IPMK function significantly impacts production of downstream HOIPs such as InsP4, InsP5, InsP6, InsP7, and InsP8.

    “IPMK acts as a rate-limiting enzyme, with its loss of function significantly impacting the production of downstream HOIPs such as InsP4, InsP5, InsP6, InsP7, and InsP8 [13,14].”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [14]

    The Introduction (page unavailable) says IPMK generates IP4 and IP5, and describes their pathway toward IP6, IP7, and IP8. The Results section on autophagy (page unavailable) reports inositol profiling to verify kinase activity, but our copy does not state that loss of IPMK significantly reduces production of all five compounds or that IPMK is rate-limiting. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Studies across various organisms demonstrated a significant decrease in both InsP5 and InsP6 production in IPMK-null or kinase-dead cells.

    “Studies across various organisms, from yeast to mammalian cells, have demonstrated a significant decrease in both InsP5 and InsP6 production in IPMK-null or kinase-dead cells [12,14].”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [14]

    The Introduction (page unavailable) says IPMK generates IP5 and describes a pathway leading to IP6. The Results section ‘IPMK Is Essential for Autophagy’ (page unavailable) identifies a kinase-dead IPMK mutant and reports inositol profiling, but the available text does not report a significant decrease in both InsP5 and InsP6 production in IPMK-null or kinase-dead cells across organisms. (LLM, conf=0.79)

    Experimental — accuracy not yet measured

  • When IPMK is deleted, InsP5 and InsP6 concentrations within cells show a notable reduction.

    “When IPMK is deleted, InsP5 and InsP6 concentrations within cells show a notable reduction, highlighting its importance in maintaining these HOIPs [14].”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [14]

    The Introduction (page unavailable) says IPMK physiologically generates IP5 and describes the pathway leading to IP6. The Results mention inositol profiling (page unavailable), but our copy does not report a notable reduction in cellular IP5 or IP6 concentrations after IPMK deletion. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

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Cites

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Cited by

Sorted by citations

Authors
Guha, P., Tyagi, R., Chowdhury, S., Reilly, L., Fu, C., Xu, R., Resnick, A. C., & Snyder, S. H.
Affiliations
  • Johns Hopkins University (US)
  • Children's Hospital of Philadelphia (US)
Corresponding author
Snyder, Solomon H.
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2019-03
Volume
26
Issue
10
Pages
2692-2703.e7
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2019.02.013
PMC
PMC6494083
OpenAlex
W2919253735
Cited by
48
References
7
Citations by year
2026: 5 · 2025: 8 · 2024: 5 · 2023: 6 · 2022: 9 · 2021: 3 · 2020: 7 · 2019: 5
FWCI
4.57
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion, cc-by)
  • PubMed Central (acceptedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
NIH (5R01MH018501-48)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
inositol polyphosphate multikinase, autophagy, lipophagy, liver inflammation, hepatocyte regeneration, AMPK, SIRT1, ULK1, histone deacetylation, ternary complex, liver injury
MeSH terms
Autophagy-Related Protein-1 Homolog, AMP-Activated Protein Kinase Kinases, Animals, Autophagy, Carcinoma, Renal Cell, Female, Hepatitis, Humans, Kidney Neoplasms, Liver, Liver Regeneration, Male, Phosphorylation, Protein Kinases, Transfection, Signal Transduction, Phosphotransferases (Alcohol Group Acceptor), Mice, Knockout, Intracellular Signaling Peptides and Proteins, Mice, Sirtuin 1, HEK293 Cells

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