bims-lypmec 2023-03-12 papers

Handb Exp Pharmacol. 2023 Mar 08.

Lysosomal Ion Channels and Lysosome-Organelle Interactions.

Weijie Cai, Ping Li, Mingxue Gu, Haoxing Xu.

Intracellular organelles exchange their luminal contents with each other via both vesicular and non-vesicular mechanisms. By forming membrane contact sites (MCSs) with ER and mitochondria, lysosomes mediate bidirectional transport of metabolites and ions between lysosomes and organelles that regulate lysosomal physiology, movement, membrane remodeling, and membrane repair. In this chapter, we will first summarize the current knowledge of lysosomal ion channels and then discuss the molecular and physiological mechanisms that regulate lysosome-organelle MCS formation and dynamics. We will also discuss the roles of lysosome-ER and lysosome-mitochondria MCSs in signal transduction, lipid transport, Ca 2+ transfer, membrane trafficking, and membrane repair, as well as their roles in lysosome-related pathologies.

Keywords: ER; Lysosomes; Membrane contact sites; Mitochondria; TRPML1

DOI: https://doi.org/10.1007/164_2023_640

J Invest Dermatol. 2023 Mar 03. pii: S0022-202X(23)00171-9. [Epub ahead of print]

Lysosomal function and intracellular position determine the malignant phenotype in malignant melanoma.

Ida Eriksson, Linda Vainikka, Petra Wäster, Karin Öllinger.

Lysosomes are central in cell homeostasis and participate in macromolecular degradation, plasma membrane repair, exosome release, cell adhesion/migration and apoptosis. In cancer, alterations in lysosomal function and spatial distribution may facilitate disease progression. In this study we show enhanced lysosomal activity in malignant melanoma cells compared to normal human melanocytes. Most lysosomes show perinuclear location in melanocytes, while they are more dispersed in melanoma, with retained proteolytic activity and low pH also in the peripheral population. Rab7a expression is lower in melanoma cells than in melanocytes and, by increasing Rab7a, lysosomes are relocated to the perinuclear region in melanoma. Exposure to the lysosome destabilizing drug LLOMe (L-leucyl-L-leucine methyl ester) causes higher damage in the perinuclear subset of lysosomes in melanomas, while difference in subpopulation susceptibility cannot be found in melanocytes. Interestingly, melanoma cells recruit the ESCRT-III core protein CHMP4B, involved in lysosomal membrane repair, rather than initiate lysophagy. However, when the perinuclear lysosomal position is promoted by Rab7a overexpression or kinesore treatment, lysophagy is increased. In addition, Rab7a-overexpression is accompanied by reduced migration capacity. Taken together, the study emphasizes that alterations in lysosomal properties facilitate the malignant phenotype and declares the targeting of lysosomal function as a future therapeutic approach.

Keywords: LMP; lysosomal positioning; lysosome; malignant melanoma; melanocytes

DOI: https://doi.org/10.1016/j.jid.2023.01.036

Proc Natl Acad Sci U S A. 2023 Mar 14. 120(11): e2213886120

Lysosome-targeted multifunctional lipid probes reveal the sterol transporter NPC1 as a sphingosine interactor.

Janathan Altuzar, Judith Notbohm, Frank Stein, Per Haberkant, Pia Hempelmann, Saskia Heybrock, Jutta Worsch, Paul Saftig, Doris Höglinger.

Lysosomes are catabolic organelles involved in macromolecular digestion, and their dysfunction is associated with pathologies ranging from lysosomal storage disorders to common neurodegenerative diseases, many of which have lipid accumulation phenotypes. The mechanism of lipid efflux from lysosomes is well understood for cholesterol, while the export of other lipids, particularly sphingosine, is less well studied. To overcome this knowledge gap, we have developed functionalized sphingosine and cholesterol probes that allow us to follow their metabolism, protein interactions, and their subcellular localization. These probes feature a modified cage group for lysosomal targeting and controlled release of the active lipids with high temporal precision. An additional photocrosslinkable group allowed for the discovery of lysosomal interactors for both sphingosine and cholesterol. In this way, we found that two lysosomal cholesterol transporters, NPC1 and to a lesser extent LIMP-2/SCARB2, bind to sphingosine and showed that their absence leads to lysosomal sphingosine accumulation which hints at a sphingosine transport role of both proteins. Furthermore, artificial elevation of lysosomal sphingosine levels impaired cholesterol efflux, consistent with sphingosine and cholesterol sharing a common export mechanism.

Keywords: lysosomal storage diseases; organelle-targeted probes; photocrosslinking; protein–lipid interaction; sphingolipids

DOI: https://doi.org/10.1073/pnas.2213886120

Nat Rev Nephrol. 2023 Mar 09.

The role of lysosomes in metabolic and autoimmune diseases.

Frédéric Gros, Sylviane Muller.

Lysosomes are catabolic organelles that contribute to the degradation of intracellular constituents through autophagy and of extracellular components through endocytosis, phagocytosis and macropinocytosis. They also have roles in secretory mechanisms, the generation of extracellular vesicles and certain cell death pathways. These functions make lysosomes central organelles in cell homeostasis, metabolic regulation and responses to environment changes including nutrient stresses, endoplasmic reticulum stress and defects in proteostasis. Lysosomes also have important roles in inflammation, antigen presentation and the maintenance of long-lived immune cells. Their functions are tightly regulated by transcriptional modulation via TFEB and TFE3, as well as by major signalling pathways that lead to activation of mTORC1 and mTORC2, lysosome motility and fusion with other compartments. Lysosome dysfunction and alterations in autophagy processes have been identified in a wide variety of diseases, including autoimmune, metabolic and kidney diseases. Deregulation of autophagy can contribute to inflammation, and lysosomal defects in immune cells and/or kidney cells have been reported in inflammatory and autoimmune pathologies with kidney involvement. Defects in lysosomal activity have also been identified in several pathologies with disturbances in proteostasis, including autoimmune and metabolic diseases such as Parkinson disease, diabetes mellitus and lysosomal storage diseases. Targeting lysosomes is therefore a potential therapeutic strategy to regulate inflammation and metabolism in a variety of pathologies.

DOI: https://doi.org/10.1038/s41581-023-00692-2

J Cell Sci. 2023 Mar 15. pii: jcs260471. [Epub ahead of print]136(6):

Membrane tethers at a glance.

Viktória Szentgyörgyi, Anne Spang.

Cargo delivery from one compartment to the next relies on the fusion of vesicles with different cellular organelles in a process that requires the concerted action of tethering factors. Although all tethers act to bridge vesicle membranes to mediate fusion, they form very diverse groups as they differ in composition, and in their overall architecture and size, as well as their protein interactome. However, their conserved function relies on a common design. Recent data on class C Vps complexes indicates that tethers play a significant role in membrane fusion beyond vesicle capturing. Furthermore, these studies provide additional mechanistic insights into membrane fusion events and reveal that tethers should be considered as key players of the fusion machinery. Moreover, the discovery of the novel tether FERARI complex has changed our understanding of cargo transport in the endosomal system as it has been shown to mediate 'kiss-and-run' vesicle-target membrane interactions. In this Cell Science at a Glance and the accompanying poster, we compare the structure of the coiled-coil and the multisubunit CATCHR and class C Vps tether families on the basis of their functional analogy. We discuss the mechanism of membrane fusion, and summarize how tethers capture vesicles, mediate membrane fusion at different cellular compartments and regulate cargo traffic.

Keywords: Endosomes; Golgi; Membrane fusion; Membrane traffic; Rab GTPase; SNARE

DOI: https://doi.org/10.1242/jcs.260471