Lysosomal recycling of amino acids affects ER quality control.

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Publication Year:
2020
Authors:
Ryo Higuchi-Sanabria, Koning Shen, Naame Kelet, Phillip A Frankino, Jenni Durieux, Raz Bar-Ziv, Cierra N Sing, Enrique J Garcia, Stefan Homentcovschi, Melissa Sanchez, Rui Wu, Sarah U Tronnes, Larry Joe, Brant Webster, Alex Ahilon-Jeronimo, Samira Monshietehadi, Sofia Dallarda, Corinne Pender, Liza A Pon, Roberto Zoncu, Andrew Dillin
PubMed ID:
32637599
Funding Grants:
Public Summary:
The lysosome is a cellular organelle often referred to as the “trashcan” of the cell due to its primary function to digest and recycle unneeded or damaged intracellular material. The endoplasmic reticulum (ER) is a vast intracellular network of membranes, which function as the manufacturing center for macromolecules of the cell. The lysosome and ER carry out critical, yet seemingly opposing, functions of catabolism and anabolism, thus it is essential that the organelles be in constant communication to ensure cellular homeostasis. However, a method of communication between the lysosome and ER has yet to be identified. In this study, we performed a genetic screen to understand what functional regulators of the lysosome impact ER homeostasis. Through these screens, we found a lysosomal amino acid transporter, LAAT-1. Specifically, LAAT-1 is involved in export of recycled lysine and arginine from the lysosome, and this process is critical for proper function of ER quality control machineries. Without LAAT-1, the ER is highly susceptible to damage. Mutations in LAAT-1 increase stress sensitivity and decrease organismal health and lifespan. Ultimately, our studies show that lysosomal recycling of key amino acids are critical for regulating ER function, which has direct implications in organismal physiology and lifespan.
Scientific Abstract:
Recent work has highlighted the fact that lysosomes are a critical signaling hub of metabolic processes, providing fundamental building blocks crucial for anabolic functions. How lysosomal functions affect other cellular compartments is not fully understood. Here, we find that lysosomal recycling of the amino acids lysine and arginine is essential for proper ER quality control through the UPR(ER). Specifically, loss of the lysine and arginine amino acid transporter LAAT-1 results in increased sensitivity to proteotoxic stress in the ER and decreased animal physiology. We find that these LAAT-1-dependent effects are linked to glycine metabolism and transport and that the loss of function of the glycine transporter SKAT-1 also increases sensitivity to ER stress. Direct lysine and arginine supplementation, or glycine supplementation alone, can ameliorate increased ER stress sensitivity found in laat-1 mutants. These data implicate a crucial role in recycling lysine, arginine, and glycine in communication between the lysosome and ER.