Cholesterol transfer via endoplasmic reticulum contacts mediates lysosome damage repair
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Cholesterol transfer via endoplasmic reticulum contacts mediates lysosome damage repair. / Radulovic, Maja; Wenzel, Eva Maria; Gilani, Sania; Holland, Lya K.K.; Lystad, Alf Håkon; Phuyal, Santosh; Olkkonen, Vesa M.; Brech, Andreas; Jäättelä, Marja; Maeda, Kenji; Raiborg, Camilla; Stenmark, Harald.
I: EMBO Journal, Bind 41, Nr. 24, e112677, 2022.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Cholesterol transfer via endoplasmic reticulum contacts mediates lysosome damage repair
AU - Radulovic, Maja
AU - Wenzel, Eva Maria
AU - Gilani, Sania
AU - Holland, Lya K.K.
AU - Lystad, Alf Håkon
AU - Phuyal, Santosh
AU - Olkkonen, Vesa M.
AU - Brech, Andreas
AU - Jäättelä, Marja
AU - Maeda, Kenji
AU - Raiborg, Camilla
AU - Stenmark, Harald
N1 - Publisher Copyright: © 2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
PY - 2022
Y1 - 2022
N2 - Lysosome integrity is essential for cell viability, and lesions in lysosome membranes are repaired by the ESCRT machinery. Here, we describe an additional mechanism for lysosome repair that is activated independently of ESCRT recruitment. Lipidomic analyses showed increases in lysosomal phosphatidylserine and cholesterol after damage. Electron microscopy demonstrated that lysosomal membrane damage is rapidly followed by the formation of contacts with the endoplasmic reticulum (ER), which depends on the ER proteins VAPA/B. The cholesterol-binding protein ORP1L was recruited to damaged lysosomes, accompanied by cholesterol accumulation by a mechanism that required VAP–ORP1L interactions. The PtdIns 4-kinase PI4K2A rapidly produced PtdIns4P on lysosomes upon damage, and knockout of PI4K2A inhibited damage-induced accumulation of ORP1L and cholesterol and led to the failure of lysosomal membrane repair. The cholesterol–PtdIns4P transporter OSBP was also recruited upon damage, and its depletion caused lysosomal accumulation of PtdIns4P and resulted in cell death. We conclude that ER contacts are activated on damaged lysosomes in parallel to ESCRTs to provide lipids for membrane repair, and that PtdIns4P generation and removal are central in this response.
AB - Lysosome integrity is essential for cell viability, and lesions in lysosome membranes are repaired by the ESCRT machinery. Here, we describe an additional mechanism for lysosome repair that is activated independently of ESCRT recruitment. Lipidomic analyses showed increases in lysosomal phosphatidylserine and cholesterol after damage. Electron microscopy demonstrated that lysosomal membrane damage is rapidly followed by the formation of contacts with the endoplasmic reticulum (ER), which depends on the ER proteins VAPA/B. The cholesterol-binding protein ORP1L was recruited to damaged lysosomes, accompanied by cholesterol accumulation by a mechanism that required VAP–ORP1L interactions. The PtdIns 4-kinase PI4K2A rapidly produced PtdIns4P on lysosomes upon damage, and knockout of PI4K2A inhibited damage-induced accumulation of ORP1L and cholesterol and led to the failure of lysosomal membrane repair. The cholesterol–PtdIns4P transporter OSBP was also recruited upon damage, and its depletion caused lysosomal accumulation of PtdIns4P and resulted in cell death. We conclude that ER contacts are activated on damaged lysosomes in parallel to ESCRTs to provide lipids for membrane repair, and that PtdIns4P generation and removal are central in this response.
KW - cholesterol
KW - lysosome
KW - membrane contact site
KW - membrane repair
KW - phosphoinositide
U2 - 10.15252/embj.2022112677
DO - 10.15252/embj.2022112677
M3 - Journal article
C2 - 36408828
AN - SCOPUS:85143309001
VL - 41
JO - E M B O Journal
JF - E M B O Journal
SN - 0261-4189
IS - 24
M1 - e112677
ER -
ID: 330390003