Ceramide targets autophagosomes to mitochondria and induces lethal mitophagy.
Ceramide targets autophagosomes to mitochondria and induces lethal mitophagy.
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DOI：
10.1038/nchembio.1059
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发表时间：
2012-10
影响因子：
14.8
通讯作者：
Ogretmen, Besim
中科院分区：
文献类型：
--
作者：
Sentelle, R. David;Senkal, Can E.;Jiang, Wenhui;Ponnusamy, Suriyan;Gencer, Salih;Selvam, Shanmugam Panneer;Ramshesh, Venkat K.;Peterson, Yuri K.;Lemasters, John J.;Szulc, Zdzislaw M.;Bielawski, Jacek;Ogretmen, Besim
自噬促进细胞存活或死亡的机制尚不清楚。我们提供的证据表明，C18-吡啶神经酰胺(C18-PYR-Cer)治疗，或神经酰胺合成酶1(CerS1)表达产生的内源性C18-神经酰胺，介导了自噬细胞的死亡，而不依赖于细胞的凋亡。C18-神经酰胺诱导的致死性自噬通过微管相关蛋白1轻链3β脂化(LC3B-II)和含有LC3B-II的自噬溶酶体选择性靶向线粒体(线粒体内吞噬)来调节，这些作用是通过神经酰胺和LC3B-II在依赖于Drp1的线粒体分裂时直接相互作用而导致的，从而抑制线粒体的功能和耗氧量。因此，分子模拟预测，神经酰胺结合受损的突变体LC3B的表达阻止了CerS1介导的线粒体靶向，恢复了氧气消耗。此外，CerS1基因敲除了亚硒酸钠诱导的有丝分裂吞噬作用，稳定的LC3B基因敲除保护了CerS1-C18神经酰胺依赖的有丝分裂吞噬作用，并阻断了体内的肿瘤抑制。因此，这些数据表明神经酰胺具有一种新的受体功能，可以将LC3B-II-自噬溶酶体锚定在线粒体膜上，从而定义了诱导致死性有丝分裂的关键机制。
Mechanisms by which autophagy promotes cell survival or death are unclear. We provide evidence that C18-pyridinium ceramide (C18-Pyr-Cer) treatment, or endogenous C18-ceramide generation by ceramide synthase 1 (CerS1) expression mediates autophagic cell death, independent of apoptosis in human cancer cells. C18-ceramide-induced lethal autophagy was regulated via microtubule-associated protein 1 light chain 3 beta lipidation (LC3B-II) and selective targeting of mitochondria by LC3B-II-containing autophagolysosomes (mitophagy) through direct interaction between ceramide and LC3B-II upon Drp1-dependent mitochondrial fission, leading to inhibition of mitochondrial function and oxygen consumption. Accordingly, expression of mutant LC3B with impaired ceramide binding, as predicted by molecular modeling, prevented CerS1-mediated mitochondrial targeting, recovering oxygen consumption. Moreover, knockdown of CerS1 abrogated sodium selenite-induced mitophagy, and stable LC3B knockdown protected against CerS1-C18-ceramide-dependent mitophagy and blocked tumor suppression in vivo. Thus, these data suggest a novel receptor function of ceramide for anchoring LC3B-II-autophagolysosomes to mitochondrial membranes, defining a key mechanism for the induction of lethal mitophagy.
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线粒体富含神经酰胺的宏域在辐照后功能化bax。
影响因子：
3.7
作者：
Lee H;Rotolo JA;Mesicek J;Penate-Medina T;Rimner A;Liao WC;Yin X;Ragupathi G;Ehleiter D;Gulbins E;Zhai D;Reed JC;Haimovitz-Friedman A;Fuks Z;Kolesnick R
通讯作者：
Kolesnick R
DOI：
10.1073/pnas.0709191105
发表时间：
2008-01-15
影响因子：
11.1
作者：
Kudo, Norio;Kurnagai, Keigo;Kato, Ryulichi
通讯作者：
Kato, Ryulichi
影响因子：
4.8
作者：
Masud, Ali;Mohapatra, Alexander;Flavell, Richard A.
通讯作者：
Flavell, Richard A.
影响因子：
13.3
作者：
Rodriguez-Enriquez, Sara;Kim, Insil;Lemasters, John J.
通讯作者：
Lemasters, John J.
DOI：
10.1126/science.1158111
发表时间：
2008-10-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Deng X;Yin X;Allan R;Lu DD;Maurer CW;Haimovitz-Friedman A;Fuks Z;Shaham S;Kolesnick R
通讯作者：
Kolesnick R