Abstract
mTORC1 is a protein kinase important for metabolism and is regulated by growth factor and nutrient signaling pathways, mediated by the Rheb and Rag GTPases, respectively. Here we provide the first animal model in which both pathways were upregulated through concurrent mutations in their GTPase-activating proteins, Tsc1 and Depdc5. Unlike former models that induced limited mTORC1 upregulation, hepatic deletion of both Tsc1 and Depdc5 (DKO) produced strong, synergistic activation of the mTORC1 pathway and provoked pronounced and widespread hepatocyte damage, leading to externally visible liver failure phenotypes, such as jaundice and systemic growth defects. The transcriptome profile of DKO was different from single knockout mutants but similar to those of diseased human livers with severe hepatitis and mouse livers challenged with oxidative stress-inducing chemicals. In addition, DKO liver cells exhibited prominent molecular pathologies associated with excessive endoplasmic reticulum (ER) stress, oxidative stress, DNA damage and inflammation. Although DKO liver pathologies were ameliorated by mTORC1 inhibition, ER stress suppression unexpectedly aggravated them, suggesting that ER stress signaling is not the major conduit of how hyperactive mTORC1 produces liver damage. Interestingly, superoxide scavengers N-acetylcysteine (NAC) and Tempol, chemicals that reduce oxidative stress, were able to recover liver phenotypes, indicating that mTORC1 hyperactivation induced liver damage mainly through oxidative stress pathways. Our study provides a new model of unregulated mTORC1 activation through concomitant upregulation of growth factor and nutrient signaling axes and shows that mTORC1 hyperactivation alone can provoke oxidative tissue injury.
Highlights
Mammalian target of rapamycin complex 1is a protein kinase complex that promotes cellular anabolism in response to insulin/growth factor stimuli and nutrient abundance[1,2,3,4]
Immunoblot analyses of two-month-old mouse liver indicated that Alb-Cre/Depdc5F/F (Depdc5Δhep) mice lost hepatic Depdc[5] expression and slightly upregulated the level of phosphorylated S6 (p-S6), a downstream marker of Mammalian target of rapamycin complex 1 (mTORC1) (Fig. 1a)
Hematoxylin and eosin (H&E) staining of liver sections revealed that two-month-old Depdc5Δhep mice had specific enlargement of pericentral zone 3 hepatocytes (Fig. 1b and Supplementary Fig. S1a), associated with locally elevated levels of p-S6 immunostaining (Fig. 1c and Supplementary Fig. S1a)
Summary
Mammalian target of rapamycin complex 1 (mTORC1). Is a protein kinase complex that promotes cellular anabolism in response to insulin/growth factor stimuli and nutrient abundance[1,2,3,4]. Regulation of mTORC1 is believed to be mediated by two small G proteins, Rheb and Rag[4,5]. The tuberous sclerosis complex (TSC) and the GAP activities Towards Rags 1 complex (GATOR1) are GTPase-activating proteins (GAPs) that regulate Rheb and Rag, respectively[4,5]. TSC, consisting of the TSC1 and TSC2 proteins, mediates growth factor and energy signals to mTORC16,7, while GATOR1, consisting of DEPDC5, NPRL2 and NPRL3 proteins are essential for amino acid sensing[8,9] and stress response[10] of the mTORC1 pathway. Genetic variations in the DEPDC5 locus were associated with hepatitis C virus (HCV)-induced hepatocellular carcinoma in a Japanese population[13], Cho et al Cell Discovery (2019)5:60
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