Modulation of the mevalonate pathway by akt regulates macrophage survival and development of pulmonary fibrosis.
Protein kinase B (Akt) is a key effector of multiple cellular processes, including cell survival. Akt, a serine/threonine kinase, is known to increase cell survival by regulation of the intrinsic pathway for apoptosis. In this study, we found that Akt modulated the mevalonate pathway, which is also linked to cell survival, by increasing Rho GTPase activation. Akt modulated the pathway by phosphorylating mevalonate diphosphate decarboxylase (MDD) at Ser(96). This phosphorylation in macrophages increased activation of Rac1, which enhanced macrophage survival because mutation of MDD (MDDS96A) induced apoptosis. Akt-mediated activation in macrophages was specific for Rac1 because Akt did not increase activity of other Rho GTP-binding proteins. The relationship between Akt and Rac1 was biologically relevant because Akt(+/-) mice had significantly less active Rac1 in alveolar macrophages, and macrophages from Akt(+/-) mice had an increase in active caspase-9 and -3. More importantly, Akt(+/-) mice were significantly protected from the development of pulmonary fibrosis, suggesting that macrophage survival is associated with the fibrotic phenotype. These observations for the first time suggest that Akt plays a critical role in the development and progression of pulmonary fibrosis by enhancing macrophage survival via modulation of the mevalonate pathway.
From the Department of Radiation Oncology and Program in Free Radical and Radiation Biology.
Jennifer L
JL
Larson-Casey
the Department of Internal Medicine, Carver College of Medicine, and.
Shubha
S
Murthy
the Department of Internal Medicine, Carver College of Medicine, and.
Alan J
AJ
Ryan
From the Department of Radiation Oncology and Program in Free Radical and Radiation Biology, the Department of Internal Medicine, Carver College of Medicine, and the Department of Human Toxicology, College of Public Health, University of Iowa, Iowa City, Iowa 52242 and the Iowa City Veterans Affairs Health Care System, Iowa City, Iowa 52242 brent-carter@uiowa.edu.
A Brent
AB
Carter
D000595:Amino Acid Sequence; D000818:Animals; D053898:Biosynthetic Pathways; D016764:Cell Polarity; D002470:Cell Survival; D002478:Cells, Cultured; D004789:Enzyme Activation; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000502:physiology*; D008798:Mevalonic Acid / Q000378:metabolism*; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D011658:Pulmonary Fibrosis / Q000201:enzymology* / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D009479:Neuropeptides; C484602:Rac1 protein, mouse; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D006861:Hydrogen Peroxide; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D020830:rac1 GTP-Binding Protein; D008798:Mevalonic Acid
Akt PKB; Apoptosis; Fibrosis; Macrophage; Oxidative Stress; Ras-related C3 Botulinum Toxin Substrate 1 (Rac1)