The G Protein-Coupled Taste Receptor T1R1/T1R3 Regulates mTORC1 and Autophagy.
ABSTRACT Cells continually assess their energy and nutrient state to maintain growth and survival and engage necessary homeostatic mechanisms. Cell-autonomous responses to the fed state require the surveillance of the availability of amino acids and other nutrients. The mammalian target of rapamycin complex 1 (mTORC1) integrates information on nutrient and amino acid availability to support protein synthesis and cell growth. We identify the G protein-coupled receptor (GPCR) T1R1/T1R3 as a direct sensor of the fed state and amino acid availability. Knocking down this receptor, which is found in most tissues, reduces the ability of amino acids to signal to mTORC1. Interfering with this receptor alters localization of mTORC1, downregulates expression of pathway inhibitors, upregulates key amino acid transporters, blocks translation initiation, and induces autophagy. These findings reveal a mechanism for communicating amino acid availability through a GPCR to mTORC1 in mammals.
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ABSTRACT: The ability to sense and respond to fluctuations in environmental nutrient levels is a requisite for life. Nutrient scarcity is a selective pressure that has shaped the evolution of most cellular processes. Different pathways that detect intracellular and extracellular levels of sugars, amino acids, lipids and surrogate metabolites are integrated and coordinated at the organismal level through hormonal signals. During food abundance, nutrient-sensing pathways engage anabolism and storage, whereas scarcity triggers homeostatic mechanisms, such as the mobilization of internal stores through autophagy. Nutrient-sensing pathways are commonly deregulated in human metabolic diseases.Nature 01/2015; 517(7534):302-10. DOI:10.1038/nature14190 · 42.35 Impact Factor
Article: Metabolic Control of Autophagy[Show abstract] [Hide abstract]
ABSTRACT: Macroautophagy (herein referred to as autophagy) is an evolutionarily conserved mechanism of adaptation to adverse microenvironmental conditions, including limited nutrient supplies. Several sensors interacting with the autophagic machinery have evolved to detect fluctuations in key metabolic parameters. The signal transduction cascades operating downstream of these sensors are highly interconnected to control a spatially and chronologically coordinated autophagic response that maintains the health and function of individual cells while preserving organismal homeostasis. Here, we discuss the physiological regulation of autophagy by metabolic circuitries, as well as alterations of such control in disease. Copyright © 2014 Elsevier Inc. All rights reserved.Cell 12/2014; 159(6):1263-1276. DOI:10.1016/j.cell.2014.11.006 · 33.12 Impact Factor
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ABSTRACT: The sense of taste facilitates the recognition of beneficial or potentially harmful food constituents prior to ingestion. For the detection of tastants, epithelial specializations in the oral cavity are equipped with taste receptor molecules that interact with sweet, umami (the taste of l-amino acids), salty, sour, and bitter-tasting substances. Over the past years, numerous tissues in addition to gustatory sensory tissue have been identified to express taste receptor molecules. These findings bear important implications for the roles taste receptors fulfill in vertebrates, which are currently envisioned much broader than thought previously. Taste receptive molecules are present in the brain, respiratory and gastrointestinal tracts, heart, male reproductive tissue, as well as other areas of the body just beginning to emerge. This review summarizes current knowledge on the occurrence and functional implications of taste receptive molecules outside the oral cavity.Topics in Medicinal Chemistry, 10/2014; Springer Berlin Heidelberg.