Lysosome: The metabolic signaling hub

Abstract

For the past five decades, the lysosome has been characterized as an unglamorous cellular recycling center. This notion has undergone a radical shift in the last 10 years, with new research revealing that this organelle serves as a major hub for metabolic signaling pathways. The discovery that master growth regulators, including the protein kinase mTOR (mechanistic target of rapamycin), make their home at the lysosomal surface has generated intense interest in the lysosome's key role in nutrient sensing and cellular homeostasis. The transcriptional networks required for lysosomal maintenance and function are just being unraveled and their connection to lysosome-based signaling pathways revealed. The catabolic and anabolic pathways that converge on the lysosome connect this organelle with multiple facets of cellular function; when these pathways are deregulated they underlie multiple human diseases, and promote cellular and organismal aging. Thus, understanding how lysosome-based signaling pathways function will not only illuminate the fascinating biology of this organelle but will also be critical in unlocking its therapeutic potentials.

Keywords: autophagy; lysosome; mTORC1; metabolic signaling.

Figure 1.. Regulation of mTORC1 Activity at the Lysosome by Amino Acids and Growth Factors.

(A) In the absence of amino acids the lysosomal platform comprised of the Rag GTPases and its scaffold the Ragulator complex are inactive resulting in the cytoplasmic localization of mTORC1. GATOR1, which is localized to the lysosome by KICKSTOR and activated by SAMTOR, inactivates RagA/B. GATOR2, a negative regulator of GATOR1, is inactivated by the Sestrin and CASTOR complexes. The absence of growth factor (e.g. insulin) signaling promotes the localization of the tuberous sclerosis complex (TSC) to the lysosome. (B) Amino acid stimulation results in the inhibition of GATOR1 through multiple pathways. First, methionine catabolism raises cellular levels of SAM, which promotes the disassociation of SAMTOR from GATOR1. Secondly, binding of leucine by Sestrin and arginine by CASTOR results in the dissociation of these inhibitors from GATOR2, which is therefore free to inhibit GATOR1 activity. Amino acids also stimulate the Ragulator/SLC38A9/v-ATPase complex and FLCN to activate RagA/B and RagC/D, respectively. The active Rag heterodimer recruits mTORC1 to the lysosomal surface. MCRS1 recruits the small GTPase Rheb in an amino acid dependent manner. At the lysosome, TSC’s GAP activity inhibits Rheb, and thus mTORC1 remains inactive. (C) Insulin induces TSC to leave the lysosome, permitting Rheb to bind to GTP. GTP-bound Rheb activates the kinase activity of mTORC1. Adapted and updated from (18) with permission from Elsevier.