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Global transcriptome analysis of Autophagy and mTOR pathway activation by Influenza A virus in lung A549 cells

ABSTRACT: Here we compare transcriptome dynamics in human lung carcinoma cells A549 infected with Influenza virus A/Port Chalmers/1/73 (H3N2) at two different virus to host cell ratios: multiplicity of infection (MOI) 1 and 5. Our goal was to outline the activation profiles of two main host pro-survival mechanisms, autophagy and mTORC2, co-opted by the virus to effectively complete the replication cycle, amplify, and release of infectious particles. We found that at high virus load MOI5 autophagy, a stress response mechanisms that postpones mammalian cell death, was activated and inhibited within 1 hour of infection. Autophagy downregulation was quickly followed by the activation of genes regulating mTORC2, a secondary cell survival mechanism promoting low capacity of cellular metabolism by inhibition of mTORC1, a main regulator of protein synthesis activating ribosomal elongation factors. At lower MOI (1) autophagy activation followed the virus replication cycle. We found that ULK1 gene expression was gradually upregulated upon Influenza virus A infection at MOI1 together with the activation of key regulators of mTORC1. Such results was not expected since mTORC1 inhibits autophagy activation pathway on post-transcription level through phosphorylation of ULK1.

ORGANISM(S): Influenza A virus (A/Port Chalmers/1/1973(H3N2)) Homo sapiens

PROVIDER: GSE162295 | GEO | 2020/11/29

REPOSITORIES: GEO

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Project description:DallePezze2016 - Activation of AMPK and mTOR by amino acids (Model 1) This model is as described in Supplementary Software 2 of the reference publication: SBML model including only the canonical amino acid input on mTORC1. This model is described in the article: A systems study reveals concurrent activation of AMPK and mTOR by amino acids. Dalle Pezze P, Ruf S, Sonntag AG, Langelaar-Makkinje M, Hall P, Heberle AM, Razquin Navas P, van Eunen K, Tölle RC, Schwarz JJ, Wiese H, Warscheid B, Deitersen J, Stork B, Fäßler E, Schäuble S, Hahn U, Horvatovich P, Shanley DP, Thedieck K. Nat Commun 2016 Nov; 7: 13254 Abstract: Amino acids (aa) are not only building blocks for proteins, but also signalling molecules, with the mammalian target of rapamycin complex 1 (mTORC1) acting as a key mediator. However, little is known about whether aa, independently of mTORC1, activate other kinases of the mTOR signalling network. To delineate aa-stimulated mTOR network dynamics, we here combine a computational-experimental approach with text mining-enhanced quantitative proteomics. We report that AMP-activated protein kinase (AMPK), phosphatidylinositide 3-kinase (PI3K) and mTOR complex 2 (mTORC2) are acutely activated by aa-readdition in an mTORC1-independent manner. AMPK activation by aa is mediated by Ca2+/calmodulin-dependent protein kinase kinase ? (CaMKK?). In response, AMPK impinges on the autophagy regulators Unc-51-like kinase-1 (ULK1) and c-Jun. AMPK is widely recognized as an mTORC1 antagonist that is activated by starvation. We find that aa acutely activate AMPK concurrently with mTOR. We show that AMPK under aa sufficiency acts to sustain autophagy. This may be required to maintain protein homoeostasis and deliver metabolite intermediates for biosynthetic processes. This model is hosted on BioModels Database and identified by: MODEL1705030000. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Global transcriptome analysis of Autophagy and mTOR pathway activation by Influenza A virus in lung A549 cells

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