title: Dengue Virus Activates the AMP Kinase-mTOR Axis To Stimulate a Proviral Lipophagy.
abstract: Robust dengue virus (DENV) replication requires lipophagy, a selective autophagy that targets lipid droplets. The autophagic mobilization of lipids leads to increased β-oxidation in DENV-infected cells. The mechanism by which DENV induces lipophagy is unknown. Here, we show that infection with DENV activates the metabolic regulator 5' adenosine-monophosphate activated kinase (AMPK), and that the silencing or pharmacological inhibition of AMPK activity decreases DENV replication and the induction of lipophagy. The activity of the mechanistic target of rapamycin complex 1 (mTORC1) decreases in DENV-infected cells and is inversely correlated with lipophagy induction. Constitutive activation of mTORC1 by depletion of tuberous sclerosis complex 2 (TSC2) inhibits lipophagy induction in DENV-infected cells and decreases viral replication. While AMPK normally stimulates TSC2-dependent inactivation of mTORC1 signaling, mTORC1 inactivation is independent of AMPK activation during DENV infection. Thus, DENV stimulates and requires AMPK signaling as well as AMPK-independent suppression of mTORC1 activity for proviral lipophagy.IMPORTANCEDengue virus alters host cell lipid metabolism to promote its infection. One mechanism for altered metabolism is the induction of a selective autophagy that targets lipid droplets, termed lipophagy. Lipophagy mobilizes lipid stores, resulting in enhanced β-oxidation and viral replication. We show here that DENV infection activates and requires the central metabolic regulator AMPK for its replication and the induction of lipophagy. This is required for the induction of lipophagy, but not basal autophagy, in DENV-infected cells.
authors.affiliation: Department of Microbiology, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Tristan X
authors.initials: TX
authors.lastname: Jordan
authors.affiliation: Department of Microbiology, The University of Chicago, Chicago, Illinois, USA grandall@bsd.uchicago.edu.
authors.forename: Glenn
authors.initials: G
authors.lastname: Randall
mesh_terms: D000263:Adenylate Kinase / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy; D004261:DNA Replication; D003716:Dengue Virus / Q000502:physiology*; D015967:Gene Expression Regulation, Viral; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D011533:Proviruses / Q000502:physiology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics; D014771:Virion / Q000378:metabolism; D014779:Virus Replication
chemical_list: D046912:Multiprotein Complexes; C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D000263:Adenylate Kinase
keywords: autophagy; lipid metabolism