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.