死亡受體的信號(hào)通路圖

死亡受體(death receptor)包括多種分子。有關(guān)死亡受體及其配體的研究是目前細(xì)胞凋亡 研究的熱點(diǎn)之一。死亡受體均屬TNFR 基因超家族，它們有相似的富含半胱氨酸的胞外結(jié)構(gòu)域。死亡受體都含有同源的胞漿內(nèi)序列，稱為死亡結(jié)構(gòu)域(death domain)或死亡區(qū)，其主要功能是介導(dǎo)死亡受體誘發(fā)的細(xì)胞凋亡。目前所知的死亡受體主要有Fas、TNFR1、CAR1、NGFR、DR3、DR4、DR5 等。激活這些受體的配體為T(mén)NF 基因超家族，有FasL、TNF、Apo3L、Apo-2L(TNF 相關(guān)凋亡誘導(dǎo)配體)等，還不斷有新的配體發(fā)現(xiàn)。死亡配體與死亡受體結(jié)合，通過(guò)死亡結(jié)構(gòu)域激發(fā)細(xì)胞凋亡機(jī)制。

Apoptosis is specifically induced via signaling through a family of receptors known collectively as ?death receptorsó including Fas, TNFR, DR3, DR4 and DR5. Death receptor ligands characteristically initiate signaling via receptor oligomerization, recruitment of specialized adaptor proteins and activation of caspase cascades. FasL binding induces Fas trimerization and recruits initiator caspase 8 via the adapter protein FADD. Caspase 8 then oligomerizes and is activated via autocatalysis. Activated caspase 8 stimulates apoptosis via two parallel cascades: it directly cleaves and activates caspase-3, and it cleaves Bid (a Bcl-2 family protein). Truncated Bid (tBid) translocates to mitochondria, inducing cytochrome c release, which sequentially activates caspases 9 and 3. TNF and DR-3L can deliver pro- or anti-apoptotic signals. TNFR and DR3 promote apoptosis via the adaptor proteins TRADD/FADD and the activation of caspase 8. Alternatively, apoptosis is inhibited via an adaptor protein complex including RIP which activates NF-áB and induces survival genes including IAP. Induction of apoptosis via Apo2L requires caspase activity, but the adaptor requirement is unclear.