title: CaMKIV-dependent preservation of mTOR expression is required for autophagy during lipopolysaccharide-induced inflammation and acute kidney injury.
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.
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213;
authors: Xianghong
authors: X
authors: Zhang
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213;
authors: Gina M
authors: GM
authors: Howell
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213;
authors: Lanping
authors: L
authors: Guo
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213;
authors: Richard D
authors: RD
authors: Collage
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213; Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15213; and.
authors: Patricia A
authors: PA
authors: Loughran
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213;
authors: Brian S
authors: BS
authors: Zuckerbraun
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213; Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213 rosengartmr@upmc.edu.
authors: Matthew R
authors: MR
authors: Rosengart
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D044783:F-Box Proteins / Q000235:genetics / Q000276:immunology; D000073979:F-Box-WD Repeat-Containing Protein 7; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000276:immunology; D000071679:Glycogen Synthase Kinase 3 beta; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology
chemical_list: D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513272:Fbxw7 protein, mouse; D015850:Interleukin-6; D008070:Lipopolysaccharides; C440499:lipopolysaccharide, Escherichia coli O111 B4; D044767:Ubiquitin-Protein Ligases; C546843:mTOR protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D058570:TOR Serine-Threonine Kinases; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; C517685:Camk4 protein, mouse; D038362:Glycogen Synthase Kinase 3