Amino acids and mTORC1: From lysosomes to disease

ArticleinTrends in Molecular Medicine 18(9):524-33 · June 2012with25 Reads
DOI: 10.1016/j.molmed.2012.05.007 · Source: PubMed
Abstract
The mechanistic target of rapamycin (mTOR) kinase controls growth and metabolism, and its deregulation underlies the pathogenesis of many diseases, including cancer, neurodegeneration, and diabetes. mTOR complex 1 (mTORC1) integrates signals arising from nutrients, energy, and growth factors, but how exactly these signals are propagated await to be fully understood. Recent findings have placed the lysosome, a key mediator of cellular catabolism, at the core of mTORC1 regulation by amino acids. A multiprotein complex that includes the Rag GTPases, Ragulator, and the v-ATPase forms an amino acid-sensing machinery on the lysosomal surface that affects the decision between cell growth and catabolism at multiple levels. The involvement of a catabolic organelle in growth signaling may have important implications for our understanding of mTORC1-related pathologies.
    • "Milk exosomal microRNAs and TGFβ attenuate DNA methyltransferase (DNMT) expression promoting TSDR demethylation (AAs: amino acids; ω3‑FAs; ω‑3 fatty acids; HMO: human milk oligosaccacharides; I: insulin; IGF1: insulin‑like growth factor‑1; miRs: microRNA‑148a, microRNA‑29, microRNA‑21; mTORC1: mechanistic target of rapamycin complex 1; TGFβ: transforming growth factor‑β; STAT3: signal transducer and activator of transcription 3; TSDR: Treg‑specific demethylated region) Page 3 of 9 Melnik et al. Clin Transl Allergy (2016) 6:18 glutamine increases the activity of the nutrient-sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1) [45][46][47]. Milk has recently been identified as a signalling system of mammalian evolution controlling mTORC1-dependent translation [48, 49]. Enhanced mTORC1 activity was found in the brain and ileum of mice with cow's milk allergy (CMA) [50]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Breastfeeding has protective effects for the development of allergies and atopy. Recent evidence underlines that consumption of unboiled farm milk in early life is a key factor preventing the development of atopic diseases. Farm milk intake has been associated with increased demethylation of FOXP3 and increased numbers of regulatory T cells (Tregs). Thus, the questions arose which components of farm milk control the differentiation and function of Tregs, critical T cell subsets that promote tolerance induction and inhibit the development of allergy and autoimmunity. Findings Based on translational research we identified at least six major signalling pathways that could explain milk’s biological role controlling stable FoxP3 expression and Treg differentiation: (1) via maintaining appropriate magnitudes of Akt-mTORC1 signalling, (2) via transfer of milk fat-derived long-chain ω-3 fatty acids, (3) via transfer of milk-derived exosomal microRNAs that apparently decrease FOXP3 promoter methylation, (4) via transfer of exosomal transforming growth factor-β, which induces SMAD2/SMAD3-dependent FoxP3 expression, (5) via milk-derived Bifidobacterium and Lactobacillus species that induce interleukin-10 (IL-10)-mediated differentiation of Tregs, and (6) via milk-derived oligosaccharides that serve as selected nutrients for the growth of bifidobacteria in the intestine of the new born infant. Conclusion Accumulating evidence underlines that milk is a complex signalling and epigenetic imprinting network that promotes stable FoxP3 expression and long-lasting Treg differentiation, crucial postnatal events preventing atopic and autoimmune diseases.
    Full-text · Article · Dec 2016
    • "Therefore, we performed a cellular GWAS screen to define human variation in the Hapmap B cell-derived immunoblast response to rapamycin (sirolimus), a clinical immunosuppressant. Rapamycin stimulates autophagy, a cellular homeostasis pathway important in thymic selection of T cells, survival of B cells, immune tolerance, and antigen presentation, by the inhibition of mammalian target of rapamycin (mTOR) complexes [3] . Autophagy is critical to antigen presentation and the development of acquired and innate immune responses, indicating that understanding common differences in human autophagy could inform about vaccine efficacy and autoimmunity. "
    [Show abstract] [Hide abstract] ABSTRACT: Mutations in genes encoding autophagy proteins have been associated with human autoimmune diseases, suggesting that diversity in autophagy responses could be associated with disease susceptibility or severity. A cellular genome-wide association study (GWAS) screen was performed to explore normal human diversity in responses to rapamycin, a microbial product that induces autophagy. Cells from several human populations demonstrated variability in expression of a cell surface receptor, CD244 (SlamF4, 2B4), that correlated with changes in rapamycin-induced autophagy. High expression of CD244 and receptor activation with its endogenous ligand CD48 inhibited starvation- and rapamycin-induced autophagy by promoting association of CD244 with the autophagy complex proteins Vps34 and Beclin-1. The association of CD244 with this complex reduced Vps34 lipid kinase activity. Lack of CD244 is associated with auto-antibody production in mice, and lower expression of human CD244 has previously been implicated in severity of human rheumatoid arthritis and systemic lupus erythematosus, indicating that increased autophagy as a result of low levels of CD244 may alter disease outcomes.
    Full-text · Article · Jun 2016
    • "Taken together, the accumulation of unprocessed endolysosomal content in GPR65-null cells supports a partial lysosomal degradative defect in these cells. GPR65 Crohn's Disease Risk Variant Alters Lysosomal Activity Consistent with our observation of aberrant lysosome accumulation in GPR65-null cells, an unbiased genome-wide analysis of gene expression differences between WT and Gpr65 À/À BMDMs identified differential regulation of genes implicated in lysosomal function (Atp6v1d and Atp6v1e1) and vesicular transport (Snx10), suggesting potential dysregulation of these processes (Figure S5A; Efeyan et al., 2012; Qin et al., 2006). Atp6v1d and Atp6v1e1, two of the genes downregulated in Gpr65 À/À cells, encode subunits of the H + transporting vacuolar ATPase (V-ATPase) that functions to acidify lysosomes as well as other intracellular compartments. "
    [Show abstract] [Hide abstract] ABSTRACT: Although numerous polymorphisms have been associated with inflammatory bowel disease (IBD), identifying the function of these genetic factors has proved challenging. Here we identified a role for nine genes in IBD susceptibility loci in antibacterial autophagy and characterized a role for one of these genes, GPR65, in maintaining lysosome function. Mice lacking Gpr65, a proton-sensing G protein-coupled receptor, showed increased susceptibly to bacteria-induced colitis. Epithelial cells and macrophages lacking GPR65 exhibited impaired clearance of intracellular bacteria and accumulation of aberrant lysosomes. Similarly, IBD patient cells and epithelial cells expressing an IBD-associated missense variant, GPR65 I231L, displayed aberrant lysosomal pH resulting in lysosomal dysfunction, impaired bacterial restriction, and altered lipid droplet formation. The GPR65 I231L polymorphism was sufficient to confer decreased GPR65 signaling. Collectively, these data establish a role for GPR65 in IBD susceptibility and identify lysosomal dysfunction as a potentially causative element in IBD pathogenesis with effects on cellular homeostasis and defense.
    Article · Jun 2016
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