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CaMKIV-Dependent Preservation of mTOR Expression Is Required for Autophagy during Lipopolysaccharide-Induced Inflammation and Acute Kidney Injury

Xianghong Zhang, Gina M. Howell, Lanping Guo, Richard D. Collage, Patricia A. Loughran, Brian S. Zuckerbraun and Matthew R. Rosengart
J Immunol September 1, 2014, 193 (5) 2405-2415; DOI: https://doi.org/10.4049/jimmunol.1302798
Xianghong Zhang
*Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213;
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Gina M. Howell
*Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213;
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Lanping Guo
*Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213;
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Richard D. Collage
*Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213;
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Patricia A. Loughran
*Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213;
†Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15213; and
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Brian S. Zuckerbraun
*Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213;
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Matthew R. Rosengart
*Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213;
‡Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213
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Abstract

Autophagy, an evolutionarily conserved homeostasis process regulating biomass quantity and quality, plays a critical role in the host response to sepsis. Recent studies show its calcium dependence, but the calcium-sensitive regulatory cascades have not been defined. In this study, we describe a novel mechanism in which calcium/calmodulin-dependent protein kinase IV (CaMKIV), through inhibitory serine phosphorylation of GSK-3β and inhibition of FBXW7 recruitment, prevents ubiquitin proteosomal degradation of mammalian target of rapamycin (mTOR) and thereby augments autophagy in both the macrophage and the kidney. Under the conditions of sepsis studied, mTOR expression and activity were requisite for autophagy, a paradigm countering the current perspective that prototypically, mTOR inhibition induces autophagy. CaMKIV–mTOR-dependent autophagy was fundamentally important for IL-6 production in vitro and in vivo. Similar mechanisms were operant in the kidney during endotoxemia and served a cytoprotective role in mitigating acute kidney injury. Thus, CaMKIV–mTOR-dependent autophagy is conserved in both immune and nonimmune/parenchymal cells and is fundamental for the respective functional and adaptive responses to septic insult.

Footnotes

  • This work was supported by National Institutes of Health Grant R01 GM082852 (to M.R.R.) and a Surgical Infection Society Resident Research Fellowship grant (to M.R.R.).

  • Abbreviations used in this article:

    AKI
    acute kidney injury
    AMPK
    AMP-activated protein kinase
    CaMK
    calcium/calmodulin-dependent protein kinase
    Mϕ
    macrophage
    mTOR
    mammalian target of rapamycin
    mTORC1
    mammalian target of rapamycin complex 1
    pMϕ
    peritoneal Mϕ
    RNAi
    RNA interference
    RT
    room temperature
    siRNA
    small interfering RNA
    TASCC
    TOR–autophagy spatial coupling compartment
    WT
    wild-type.

  • Received October 17, 2013.
  • Accepted June 20, 2014.
  • Copyright © 2014 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 193 (5)
The Journal of Immunology
Vol. 193, Issue 5
1 Sep 2014
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CaMKIV-Dependent Preservation of mTOR Expression Is Required for Autophagy during Lipopolysaccharide-Induced Inflammation and Acute Kidney Injury
Xianghong Zhang, Gina M. Howell, Lanping Guo, Richard D. Collage, Patricia A. Loughran, Brian S. Zuckerbraun, Matthew R. Rosengart
The Journal of Immunology September 1, 2014, 193 (5) 2405-2415; DOI: 10.4049/jimmunol.1302798

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CaMKIV-Dependent Preservation of mTOR Expression Is Required for Autophagy during Lipopolysaccharide-Induced Inflammation and Acute Kidney Injury
Xianghong Zhang, Gina M. Howell, Lanping Guo, Richard D. Collage, Patricia A. Loughran, Brian S. Zuckerbraun, Matthew R. Rosengart
The Journal of Immunology September 1, 2014, 193 (5) 2405-2415; DOI: 10.4049/jimmunol.1302798
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