A novel mechanism uncovered for lysosomal repair
Maja Radulovic and her co-workers have revealed a novel mechanism that contributes to lysosome repair, namely lipid transfer from the endoplasmic reticulum (ER)
Graphical Abstract from the publication in EMBO J.
Lysosomes are membrane-bound cell organelles that contain digestive enzymes and serve as the main degradative compartments of cells. They play crucial roles in energy metabolism, homeostasis, signaling and immunity. Lysosomal membrane breakage or full rupture of lysosomes is a common and severe stress condition that is relevant for degenerative disease, infection, and cancer. These compartments are also interesting in the context of cancer therapy since they contain compounds that tend to kill cells when released, a concept that is being investigated for selective killing of cancer cells with lysosome-disrupting drugs. To make lysosome-targeted killing of cancer cells more effective, it is important to understand the biology of the lysosome membrane.
Maja Radulovic, postdoc in Harald Stenmark's group at the Institute for Cancer Research and Center for Cancer Cell Reprogramming, has previously shown that a molecular machinery known as ESCRT contributes to repair damaged lysosomes. However, when ESCRT is depleted, lysosomes can still be repaired. This suggests that additional repair mechanisms exist.
Now, Maja and her co-workers have revealed an additional mechanism that contributes to lysosome repair, namely lipid transfer from the endoplasmic reticulum (ER). Upon lysosome damage, the enzyme PI4K2A is activated to produce a specific lipid, PtdIns4P, on the lysosome membrane, and this lipid in turn recruits a protein, ORP1L, which forms contact sites between the damaged lysosome and the ER. ORP1L then shuttles cholesterol, produced by the ER, from the ER membrane to the lysosome membrane to promote its healing. Thus this study identifies a new mechanism where damaged lysosomes must contact the ER to receive lipids for repair. In the future it might be possible to target ESCRT- or ER-mediated lysosome repair in cancer cells to promote their death.
Further readings -
Cholesterol transfer via endoplasmic reticulum contacts mediates lysosome damage repair.
Radulovic M, Wenzel EM, Gilani S, Holland LK, Lystad AH, Phuyal S, Olkkonen VM, Brech A, Jäättelä M, Maeda K, Raiborg C, Stenmark H.
EMBO J. 2022 Nov 21:e112677. doi: 10.15252/embj.2022112677. Online ahead of print. PMID: 36408828
ESCRT-mediated lysosome repair precedes lysophagy and promotes cell survival.
Radulovic M, Schink KO, Wenzel EM, Nähse V, Bongiovanni A, Lafont F, Stenmark H.
EMBO J. 2018 Nov 2;37(21):e99753. doi: 10.15252/embj.201899753. Epub 2018 Oct 12. PMID: 30314966