Palmitoylation of CD95 facilitates formation of SDS-stable receptor aggregates that initiate apoptosis signaling
Palmitoylation of CD95 facilitates formation of SDS-stable receptor aggregates that initiate apoptosis signaling
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DOI：
10.1038/sj.emboj.7601460
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发表时间：
2007-01-10
期刊：
影响因子：
11.4
通讯作者：
Peter, Marcus E.
中科院分区：
文献类型：
--
作者：
Feig, Christine;Tchikov, Vladimir;Peter, Marcus E.
细胞凋亡信号通过CD95(Fas/APO-1)参与受体的聚集和聚集，然后是肌动蛋白依赖的内化。内化是有效形成死亡诱导信号复合体(DISC)所必需的，当受体到达内体隔室时，FADD、caspase-8/10和c-flip的最大募集发生。在CD95信号传递过程中，第一个可检测到的事件是形成稳定的十二烷基硫酸钠聚集体，这可能反映了受体的强烈寡聚。我们现在证明，这些SDS稳定形式的CD95对应于超高分子量盘状复合体(HiDISC)，并且是caspase-8激活的位置。在耐洗涤剂的膜内外都可以发现hiDISCs。稳定的CD95聚集体的形成涉及CD95膜近端半胱氨酸199的棕榈酰化。半胱氨酸199突变体不再形成SDS稳定的聚集体，抑制棕榈酰化减少了CD95的内化和caspase-8的激活。我们的研究结果表明，CD95的稳定形式是启动细胞凋亡的部位，代表着在caspase激活之前通过CD95进行细胞凋亡信号传递的一个重要的早期步骤。
Apoptosis signaling through CD95 (Fas/APO-1) involves aggregation and clustering of the receptor followed by its actin-dependent internalization. Internalization is required for efficient formation of the death-inducing signaling complex (DISC) with maximal recruitment of FADD, caspase-8/ 10 and c-FLIP occurring when the receptor has reached an endosomal compartment. The first detectable event during CD95 signaling is the formation of SDS-stable aggregates likely reflecting intense oligomerization of the receptor. We now demonstrate that these SDS-stable forms of CD95 correspond to very high molecular weight DISC complexes (hiDISC) and are the sites of caspase-8 activation. hiDISCs are found both inside and outside of detergent-resistant membranes. The formation of SDS-stable CD95 aggregates involves palmitoylation of the membrane proximal cysteine 199 in CD95. Cysteine 199 mutants no longer form SDS-stable aggregates, and inhibition of palmitoylation reduces internalization of CD95 and activation of caspase-8. Our data demonstrate that SDS-stable forms of CD95 are the sites of apoptosis initiation and represent an important early step in apoptosis signaling through CD95 before activation of caspases.