Lysosomes are the main degradative compartments of cells and play crucial roles in energy metabolism, homeostasis, signalling and immunity. 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. In order 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 Institute for Cancer Research and Centre for Cancer Cell Reprogramming, has previously shown that a molecular machinery known as ESCRT contributes to repair damaged lysosomes. 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. In the future it might be possible to target ESCRT- or ER-mediated lysosome repair in cancer cells to promote their death.
EMBO J articles:
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.
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.
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