Ca(2+)-activated sphingomyelin scrambling and turnover mediate ESCRT-independent lysosomal repair.
Ca(2+)-activated sphingomyelin scrambling and turnover mediate ESCRT-independent lysosomal repair.
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DOI：
10.1038/s41467-022-29481-4
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发表时间：
2022-04-06
影响因子：
16.6
通讯作者：
Holthuis JCM
中科院分区：
文献类型：
--
作者：
Niekamp P;Scharte F;Sokoya T;Vittadello L;Kim Y;Deng Y;Südhoff E;Hilderink A;Imlau M;Clarke CJ;Hensel M;Burd CG;Holthuis JCM
溶酶体是重要的细胞器，易受不同物质的损伤。不能修复或隔离受损的溶酶体对细胞活力构成威胁。在这里，我们报告说，细胞利用鞘磷脂为基础的溶酶体修复途径，独立于ESCRT逆转潜在的致命膜损伤。各种条件扰乱细胞器的完整性触发了快速钙激活的混乱和鞘磷脂的胞质暴露。损伤溶酶体的胞质表面上的中性鞘磷脂酶对鞘磷脂的后续代谢转化促进其修复，当ESCRT功能受损时也是如此。相反，阻断胞质鞘磷脂的周转使细胞对溶酶体损伤药物更敏感。我们的数据表明，钙激活的scramblases，鞘磷脂，和中性鞘磷脂酶是一个以前未被认识到的膜修复途径的核心组成部分，细胞通过该途径保持溶酶体的功能完整性。ESCRT的激活防止了溶酶体完整性的微小扰动的潜在致命结果。在这里，作者表明，钙激活的鞘磷脂和其胞质周转混乱驱动溶酶体修复独立于ESCRT。
Lysosomes are vital organelles vulnerable to injuries from diverse materials. Failure to repair or sequester damaged lysosomes poses a threat to cell viability. Here we report that cells exploit a sphingomyelin-based lysosomal repair pathway that operates independently of ESCRT to reverse potentially lethal membrane damage. Various conditions perturbing organelle integrity trigger a rapid calcium-activated scrambling and cytosolic exposure of sphingomyelin. Subsequent metabolic conversion of sphingomyelin by neutral sphingomyelinases on the cytosolic surface of injured lysosomes promotes their repair, also when ESCRT function is compromised. Conversely, blocking turnover of cytosolic sphingomyelin renders cells more sensitive to lysosome-damaging drugs. Our data indicate that calcium-activated scramblases, sphingomyelin, and neutral sphingomyelinases are core components of a previously unrecognized membrane restoration pathway by which cells preserve the functional integrity of lysosomes. Activation of ESCRT prevents potentially lethal outcomes of minor perturbations in lysosomal integrity. Here authors show that Ca2 + -activated scrambling of sphingomyelin and its cytosolic turnover drives lysosomal repair independently of ESCRT.
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影响因子：
64.5
作者：
Katzmann, DJ;Babst, M;Emr, SD
通讯作者：
Emr, SD
影响因子：
9.2
作者：
Ellison, Cara J.;Kukulski, Wanda;Randow, Felix
通讯作者：
Randow, Felix
影响因子：
6.7
作者：
Lopez-Jimenez, Ana T.;Cardenal-Munoz, Elena;Soldati, Thierry
通讯作者：
Soldati, Thierry
影响因子：
3.4
作者：
Houben, Diane;Demangel, Caroline;Peters, Peter J.
通讯作者：
Peters, Peter J.
影响因子：
3.4
作者：
Holopainen, JM;Angelova, MI;Kinnunen, PKJ
通讯作者：
Kinnunen, PKJ