bims-lysosi 2022-06-05 papers

Issue of 2022‒06‒05
two papers selected by
Stephanie Fernandes
Max Planck Institute for Biology of Ageing

Mol Biol Cell. 2022 Jun 02. mbcE21110595T

BORC-ARL8-HOPS Ensemble is Required for Lysosomal Cholesterol Egress through NPC2.

Lysosomes receive extracellular and intracellular cholesterol and redistribute it throughout the cell. Cholesterol egress from lysosomes is critical for cholesterol homeostasis, and its failure underlies the pathogenesis of genetic disorders such as Niemann-Pick C disease. Here, we report that the BORC-ARL8-HOPS ensemble is required for egress of free cholesterol from lysosomes and for storage of esterified cholesterol in lipid droplets. Depletion of BORC, ARL8 or HOPS does not alter the localization of the lysosomal transmembrane cholesterol transporter NPC1 to degradative compartments, but decreases the association of the luminal transporter NPC2 and increases NPC2 secretion. BORC-ARL8-HOPS depletion also increases lysosomal degradation of CI-MPR, which normally sorts NPC2 to the endosomal-lysosomal system and then is recycled to the trans-Golgi network (TGN). These defects likely result from impaired HOPS-dependent fusion of endosomal-lysosomal organelles and an uncharacterized function of HOPS in CI-MPR recycling. Our study demonstrates that the BORC-ARL8-HOPS ensemble is required for cholesterol egress from lysosomes by enabling CI-MPR-dependent trafficking of NPC2 to the endosomal-lysosomal system.

DOI: https://doi.org/10.1091/mbc.E21-11-0595-T

Trends Cell Biol. 2022 May 30. pii: S0962-8924(22)00117-9. [Epub ahead of print]

Non-canonical mTORC1 signaling at the lysosome.

Gennaro Napolitano, Chiara Di Malta, Andrea Ballabio.

The mechanistic target of rapamycin complex 1 (mTORC1) signaling hub integrates multiple environmental cues to modulate cell growth and metabolism. Over the past decade considerable knowledge has been gained on the mechanisms modulating mTORC1 lysosomal recruitment and activation. However, whether and how mTORC1 is able to elicit selective responses to diverse signals has remained elusive until recently. We discuss emerging evidence for a 'non-canonical' mTORC1 signaling pathway that controls the function of microphthalmia/transcription factor E (MiT-TFE) transcription factors, key regulators of cell metabolism. This signaling pathway is mediated by a specific mechanism of substrate recruitment, and responds to stimuli that appear to converge on the lysosomal surface. We discuss the relevance of this pathway in physiological and disease conditions.

Keywords: FLCN; Rag GTPases; TFEB; lysosome; mTORC1

DOI: https://doi.org/10.1016/j.tcb.2022.04.012