程序性坏死的分子机制

Hereditas (Beijing) 2014年6月, 36(6): 519―524

综 述

收稿日期: 2013?12?19; 修回日期: 2014?03?14

基金项目:国家重大基础研究发展规划（973计划）项目（编号： 2013CB835304），全国海洋公益项目(编号： 201305016)，国家自然科学基

金项目(编号： 31170353, 31202020)和大连市科技计划项目(编号：2013E11SF056) 资助

作者简介:巴微，硕士研究生，专业方向：细胞生物学。E-mail ：chifanchoua@

通讯作者:李庆伟，教授，博士生导师，研究方向：细胞生物学。E-mail ：liqw@

逄越，副教授，硕士生导师，研究方向：细胞生物学。E-mail ：pangyue01@ DOI: 10.3724/SP.J.1005.2014.0519 网络出版时间: 2014-4-4 10:30:31

URL: /kcms/detail/11.1913.R.20140404.1030.002.html

程序性坏死(Necroptosis)的分子机制

巴微1,2, 逄越1,2, 李庆伟1,2

1. 辽宁师范大学生命科学学院, 大连116029;

2. 辽宁师范大学七鳃鳗研究中心, 大连116029

摘要: 程序性坏死(Necroptosis)是一种不同于凋亡及传统坏死的细胞程序性死亡方式, 可由肿瘤坏死因子受体

(Tumor necrosis factor receptor, TNFR)或模式识别受体(Pattern recognition receptor, PRR)调控启动。受体相互作用蛋白(Receptor-interacting protein, RIP)1和3是启动necroptosis 的两个关键蛋白, necroptosis 启动后需要一系列分子传递和执行死亡信号, 如多核苷酸二磷酸-核糖聚合酶-1(Poly(ADP-ribose) polymerase, PARP-1)、活性氧簇(Reactive oxygen species, ROS)、Ca 2+等, 这些分子破坏线粒体及其他细胞器, 最终使细胞在缺乏天冬氨酸半胱氨酸蛋白酶(Caspase)的情况下死亡。Necroptosis 细胞可将损伤相关模式分子(Damage-associated molecular patterns, DAMPs)暴露到细胞外, 被吞噬细胞识别并清除。文章对启动necroptosis 的受体分子、传递执行细胞坏死的重要分子和坏死细胞的清除过程进行了概述。

关键词: 程序性坏死; 肿瘤坏死因子受体; 受体相互作用蛋白

The molecular mechanism of necroptosis

Wei Ba 1, 2, Yue Pang 1, 2, Qingwei Li 1, 2

1. College of Life Science , Liaoning Normal University , Dalian 116029, China ;

2. Lamprey Research Center , Liaoning Normal University , Dalian 116029, China

Abstract: Programmed necrosis called necroptosis, is different from traditional necrosis and apoptosis, it has attracted considerable attention over the last few years. Necroptosis can be initiated through many factors such as tumor necrosis factor receptor (TNFR) or pattern recognition receptor (PRR), and receptor-interacting protein (RIP) 1 and 3 are two key proteins during the process. A lot of molecules have been characterized as modulators and effectors of necroptosis, includ-ing poly(ADP-ribose) polymerase (PARP-1), reactive oxygen species (ROS), Ca 2+, which can destruct mitochondria or other organelles and induce cell dead through caspase-independent pathway. Then, damage-associated molecular pattern (DAMP) molecules were released from necroptosis cells, recognized and internalized by phagocytes. Here, we briefly dis-cuss the initiation and execution of necroptosis and the clearance of death cells.

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Keywords:necroptosis; tumor necrosis factor receptor(TNFR); receptor-interacting protein

1964年, Lockshin等[1]首次提出程序性细胞死亡(Programmed cell death, PCD)的概念。PCD是指发育过程中发生的某类由特定基因调控的细胞大量死亡。同年代, Kerr等[2]在局部缺血的情况下观察到大鼠肝细胞不断地转变成由细胞质膜包裹小圆团形态, 他将这种特殊的细胞死亡方式命名为细胞凋亡(Apoptosis)。1973年, Schweichel 和Merker[3]用形态学方法将细胞死亡划分为3类：毒素处理的小鼠胚胎细胞中, 有的细胞死于异体吞噬, 有的细胞死于自噬, 还有的细胞死亡但没有发生任何吞噬现象; 这3种死亡方式分别是凋亡、自噬和坏死。细胞凋亡是受死亡信号调节并伴随天冬氨酸半胱氨酸蛋白酶(Caspase)活化的一种细胞主动自杀的死亡方式, 凋亡时细胞皱缩、核仁裂解、胞膜内陷形成多个由质膜包裹的凋亡小体, 无内含物外泄, 因此不会引发周围组织的炎症反应[4]。细胞坏死是不受基因调控的、被动的细胞死亡方式, 坏死时细胞膨胀, 质膜破裂, 细胞内含物释放到细胞外, 引起周围组织炎症反应[5]。近年来还发现了一种可被necrostain-1 (Nec-1)抑制的新的细胞死亡方式——细胞程序性坏死(Necroptosis), 这是一种既受死亡信号调控、又呈现坏死样结构特点的死亡方式[6]。与凋亡相比, ne-croptosis不形成凋亡小体, 染色质不凝聚; 与坏死相比, necroptosis受到多种基因调控, 是有规律的细胞死亡方式; 与PARP-1依赖性细胞死亡(Parthanatos)相比, necroptosis没有caspase活化[7]。参与necroptosis过程的分子包括细胞因子、病原相关模式分子(Pathogen-associated molecular patterns, PAMPs)、RIP1、RIP3、caspase广谱抑制剂(Z-Val-Ala- Asp(OMe) -fluoromethyl ketone, zVAD-fmk)、ROS、PARP-1、水解酶等。本文就参与细胞程序性坏死的有关分子及作用机制进行了综述。

1 Necroptosis的启动

Caspase被抑制的细胞受到刺激时可能引起细胞necroptosis而非凋亡[8], 如肿瘤坏死因子(Tumor necrosis factor, TNF)诱导zVAD-fmk处理过的小鼠成纤维细胞L929程序性坏死, 还能使caspase-8缺失的白血病细胞Jurkat程序性坏死。因此, 程序性坏死可能是在凋亡无法正常启动时, 细胞用来执行死亡的方式[9]。TNF、PAMPs、DNA损伤、辐射等都能引起细胞的necroptosis。不同的细胞根据其所处环境及活化程度选择凋亡或necroptosis。

1.1受体分子引起necroptosis

TNF死亡通路起始于配体与受体的结合, 参与这一通路的受体主要为死亡受体家族里包含死亡结构域的一类受体, 包括TNFR1、Fas、死亡受体3(Death receptor 3, DR3)、DR4、DR5和肿瘤坏死因子相关凋亡诱导配体(TNF-related apoptosis-inducing ligand receptor, TRAIL)等。

TNF诱导的细胞死亡需要TNF在细胞膜上与TNFR1结合, 并在细胞内招募一系列蛋白形成不同的复合体。其中, 复合体Ⅰ包括TNF受体相关死亡结构域(TNFR-associated death domain, TRADD)、RIP1、TNFR相关因子2 (TNFR-associated factor 2, TRAF2)、TRAF5、胞内凋亡蛋白抑制因子1(Cellular inhibitor of apoptosis protein 1, cIAP1)、cIAP2、泛素酶复合体。此时, 如果RIP1被泛素化, 泛素化的RIP1募集转化生长因子β激活激酶1 (Transforming growth factor-βactivated kinase 1, TAK1)、TAK 结合蛋白2 (TAK1-binding protein 2, TAB2)、TAB3, 形成TAK1-TAB2-TAB3复合物并活化NF-κB, 抑制细胞死亡[10]。TNFR1从复合体Ⅰ解离, RIP1去泛素化, 与RIP3、TRADD、Fas死亡结构域相关蛋白(Fas-associated protein via a death domain, FADD)及caspase-8形成复合体Ⅱ。在此复合体中, 如果caspase-8切割RIP1、RIP3使其失活, 细胞就通过凋亡的方式死亡; 如果caspase-8被抑制, RIP1、RIP3通过磷酸化的方式形成复合体necrosome, 启动细胞程序性坏死[5](图1)。被caspase-8切割后只保有C 末端的RIP1无法启动necroptosis; 缺少中间结构域ID的RIP1将necroptosis转变为凋亡[11]; RIP1激酶活性被抑制时, 细胞存活率增大[12], 因此, 完整的、具有激酶活性的RIP1是细胞程序性坏死的必须因

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素。细胞程序性坏死需要RIP1和RIP3的相互作用, 如在caspase-8缺失的小鼠胚胎细胞中下调RIP1或RIP3均抑制necroptosis[13]。但是近来有研究表明, RIP1、RIP3可独立启动necroptosis：FADD缺失的T细胞necroptosis中只发现RIP1活化, 小鼠巨细胞毒素在只激活RIP3的情况下诱导细胞necroptosis[14]。

RIP1在其他受体引起的细胞程序性坏死中同样

图1 TNFR1相关的信号通路(参考文献[14]并修改)

具有重要作用。淋巴毒素β受体(Lymphotoxin beta receptor, LTβR)诱导的necroptosis可能需要凋亡信号调节激酶1(Apoptosis signal-regulating kinase 1, ASK1)及其上游RIP1参与; 缺少死亡结构域的受体TNFR和肿瘤坏死因子样凋亡微弱诱导剂(Tumor necrosis factor-like weak inducer of apoptosis, TWEAK)都可以刺激内源TNF生成, 并在caspase 受到抑制时, 通过RIP1-FADD-caspase-8复合物启动necroptosis[15]; 在酸性环境下, TRAIL诱导的人结肠癌HT29细胞及肝癌HepG2细胞的凋亡将转变为RIP1依赖的necroptosis。

PRRs为固有细胞表面一类能直接识别PAMPs 的受体, 包括Toll样受体(Toll-like receptors, TLR)、NOD样受体(NOD-like receptors, NLR)等。PAMPs 为病原微生物表面特有的、结构恒定且进化保守的分子结构, 通常是病毒的双链RNA(Double-stranded RNA, dsRNA)或细菌的脂多糖( Lipopolysaccharides, LPS)。PAMPs可在多种细胞中激活PRRs引起炎症或凋亡, 但在某些情况下, PRRs也可以诱使细胞necroptosis[16]。dsRNA类似物poly(I:C)和LPS可分别活化小鼠巨噬细胞TLR3及TLR4并启动RIP3相关的necroptosis[17]; 敲除RIP1或RIP3抑制了LPS 引起的necroptosis, 因此TLR3、TLR4诱导的necroptosis可能需要RIP1、RIP3的参与。

1.2非受体分子引起necroptosis

射线照射不仅能引起细胞坏死, 还可以活化RIP1引起细胞necroptosis。X光照射肠癌细胞时, 通过激活RIP1引起细胞necroptosis[18]。Nec-1与zVAD-fmk共同作用甲状腺和肾上腺皮质癌细胞时, 能明显抑制由辐射引起的细胞死亡; 但如果细胞缺少RIP1, Nec-1就无法起到保护细胞的作用[19]。因此, RIP1在辐射引起的细胞necroptosis中同样发挥着重要作用。

2传递和执行necroptosis信号的重要分子2.1 PARP-1

多核苷酸二磷酸-核糖聚合酶(PARP)定位在细胞核内, 与DNA修复和细胞凋亡密切相关。PARP-1因识别损伤的DNA片段而被激活, 活化的PARP-1刺激线粒体释放凋亡诱导因子(Apoptosis inducing factor, AIF), AIF转移到细胞核中引起DNA凝聚、断裂, DNA的再次受损又可以活化更多的PARP-1, 导致胞质内的NAD+大量减少, 进而糖酵解作用受到抑制, 细胞内ATP水平下降引起细胞necroptosis。缺血再灌注损伤、炎症、ROS损伤等病理过程引起

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的程序性坏死通常伴随着PARP-1的活化, PARP-1主要通过破坏线粒体引起细胞死亡[20]。

1-甲基-3-硝基-1-亚硝基胍(N-methyl-N′-nitro- N-nitrosoguanidine, MNNG)破坏DNA, 继而活化PARP-1及c-Jun氨基末端激酶(c-Jun N-terminal kinase, JNK), 诱导ROS生成, 破坏线粒体膜引起细胞necroptosis。Nec-1可抑制MNNG引起的PARP-1的活化及向核转移, 但不影响PARP-1的表达[21]; TRAIL无法活化RIP1、RIP3缺失的HT29和HepG2细胞的PARP-1及诱导necroptosis[22], 因此, 在necroptosis中RIP1、RIP3可能在PARP-1上游发挥作用。

2.2 ROS

ROS为需氧细胞在代谢过程中产生的一系列活性氧簇, 包括O2-、H2O2等。细胞内ROS主要以3种方式生成：通过氧化线粒体内电子传递链中的电子生成、通过NADPH氧化酶复合物NOX1生成或是通过其他酶生成。ROS在细胞中参与细胞增殖、细胞死亡、活化基因、应答细胞因子等多个生理过程[23]。ROS通过氧化蛋白和脂质分子破坏细胞膜、影响线粒体氧化磷酸化水平及Ca2+浓度, 从而引起细胞necroptosis。研究表明, ROS参与细胞necroptosis[24], 但U937、HT29、Jurkat等细胞可以在缺少ROS的情况下引起necroptosis[25]。

2.3 Ca2+

Ca2+参与细胞程序性坏死, 如过量的Ca2+活化脂肪氧合酶(Lipoxygenase, LOXs), LOXs通过脂质过氧化作用使溶酶体膜通透化(Lysosomal membrane permeabilization, LMP)引起细胞necroptosis(图2)。缺血时, 细胞无氧呼吸引起K+、Na+、Ca2+再分配, Ca2+通过酸敏感的离子通道涌入线粒体, 过量的Ca2+刺激氧化磷酸化, 使NADH升高, 缺血再灌注之后ROS增加, 线粒体膜通透性转换(Mitochondrial permeability transition, MPT), 如果MPT在细胞内大范围发生, 细胞就会因无法得到足够的ATP而引起necroptosis[26]。TNFR与TNF结合后能使胞质内的Ca2+浓度上升、发生LMP, 随后溶酶体内的水解酶流到细胞质中参与细胞necroptosis[27]。2.4 RNS

活性氮(Reactive nitrogen species, RNS), 如NO 和超氧化氮, 在细胞内参与氧压调节及蛋白质、脂质的过氧化反应。NO可以阻断电子传递链复合物Ⅳ的生成, 使ROS增加、ATP减少。N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid, NMDA)可诱使NMDA 受体过度活化, 驱使Ca2+内流, 持续的高Ca2+浓度激活一氧化氮合酶(Nitric oxide synthase, NOS)并过量生成NO, 生成的NO迅速被氧化成超氧化氮, 超氧化氮可以破坏DNA、活化PARP-1并引起细胞necroptosis。NMDA引起的细胞程序性坏死可能需要RIP1的参与, 但此机制目前尚不清楚[28]。

图 2 启动和传递necroptosis的分子(参考文献[20]并修改)

2.5酶

磷脂酶A2(Phospholipase A2, PLA2)是特异性切割磷脂并释放出脂肪酸的酶。有研究表明, 胞质PLA2(cPLA2)参与TNF诱导的小鼠胚胎成纤维细胞L929及MEF的程序性坏死[29]。cPLA2切割包含花生四烯酸的磷脂, 释放花生四烯酸的同时引起Ca2+浓度上升。过量的Ca2+活化PLA2下游的LOXs, LOXs通过脂质过氧化作用使细胞器、细胞膜瓦解, 引起凋亡或necroptosis[30]。

钙蛋白酶是哺乳动物细胞内普遍表达的半胱氨酸蛋白酶, 通过调节Ca2+浓度间接调控其他蛋白的活性及各种信号通路。Ca2+浓度升高激活细胞质中

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钙蛋白酶的前体, 活化的钙蛋白酶特异性的切割质膜上的Na+-Ca2+通道, 导致细胞质内Ca2+浓度不可逆上升, 直至细胞死亡。

神经酰胺是鞘磷脂信号途径的中心分子, 由磷脂酶C水解鞘磷脂产生, 在维持细胞稳态, 调节细胞死亡、增殖、分化等过程起到重要作用。当细胞受到刺激时, 神经酰胺应激活化并激活JNK等多种蛋白酶, 抑制氧化磷酸化, 引起细胞necroptosis [31]。在TNF诱导的L929细胞程序性坏死中发现神经酰胺的积累, 并且TNF与zVAD-fmk共同作用时神经酰胺积累量要比只有TNF作用时多, 细胞也会更快死亡。TNF无法使RIP1缺失的Jurkat细胞、cPLA2缺失的L929细胞内神经酰胺发生变化, 因此, RIP1、cPLA2可能参与调控TNF诱导的细胞神经酰胺的积累。

3 Necroptosis细胞的处理

凋亡细胞释放溶血卵磷脂、磷脂酰丝氨酸等信号分子, 在不引起炎症反应和免疫应答的情况下, 被吞噬细胞识别、清除[32]。一些坏死状的细胞在质膜完全破裂之前, 也会把磷脂酰丝氨酸暴露在细胞表面, 以便被吞噬细胞识别。程序性坏死的细胞质膜完全破裂之后, 其胞内的DNA片段、ATP、促炎因子等DAMPs分子就会流到细胞外[33], PRRs识别这些分子激活免疫应答, 清除死亡细胞[34]。

4结语与展望

受体分子和非受体分子均可启动necroptosis, RIP1、RIP3、PARP-1、ROS、Ca2+、RNS及多种酶参与necroptosis传递和执行。RIP1是细胞程序性坏死中的关键分子, 是细胞选择凋亡或坏死的开关; RIP1、RIP3形成的复合体necrosome在程序性坏死中发挥重要作用。细胞内ROS、Ca2+、NO等含量的升高都能引起细胞necroptosis。坏死细胞的DAMPs 分子暴露之后, 可以被吞噬细胞识别清除。

细胞程序性坏死为治疗多种疾病提供了新的思路：necroptosis在促进肿瘤细胞死亡[35]、抗病毒感染上有很好的应用; 抑制细胞necroptosis还能减少心梗等疾病带来的损伤。尽管近年来对程序性坏死做了大量研究, 但是目前还没有有效的分子标记, 对necroptosis如何启动、信号如何传递、如何执行以及如何引起炎症, 这些机制都尚未清楚, 有待进一步研究。

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(责任编委: 周荣家)

程序性坏死（Necroptosis）的分子机制

作者：巴微， 逄越， 李庆伟， Wei Ba， Yue Pang， Qingwei Li

作者单位：辽宁师范大学生命科学学院，大连116029; 辽宁师范大学七鳃鳗研究中心，大连116029

刊名：

遗传

英文刊名：Hereditas

年，卷(期)：2014(6)

被引用次数：3次

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receptor 3-mediated necrosis via TRIF,RIP3,and MLKL 2013(43)

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19.Nehs MA;Lin CI;Kozono DE;Whang EE Cho NL Zhu K Moalem J Moore FD Jr Ruan DT Necroptosis is a novel mechanism of radiation-induced cell death in anap-lastic thyroid and adrenocortical cancers 2011(06)

20.Vanlangenakker N;Vanden Berghe T;Vandenabeele P Many stimuli pull the necrotic trigger,an overview 2012(01)

21.Xu X;Chua CC;Zhang M;Geng D Liu CF Hamdy RC Chua BH The role of PARP activation in glutamate-in-duced necroptosis in HT-22 cells 2010

22.Jouan-Lanhouet S;Arshad MI;Piquet-Pellorce C;Mar-tin-Chouly C Le Moigne-Muller G Van Herreweghe F Takahashi N Sergent O Lagadic-Gossmann D Vandenabeele P Samson M Dimanche-Boitrel MT TRAIL induces ne-croptosis involving RIPK1/RIPK3-dependent PARP-1 ac-tivation 2012(12)

23.Ray PD;Huang BW;Tsuji Y Reactive oxygen species(ROS)homeostasis and redox regulation in cellular sig-naling 2012(05)

24.Shindo R;Kakehashi H;Okumura K;Kumagai Y Nakano H Critical contribution of oxidative stress to TNFα-induced necroptosis downstream of RIPK1 activation 2013(02)

25.He S;Wang L;Miao L;Wang T Du F Zhao L Wang X Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha 2009(06)

26.Feissner RF;Skalska J;Gaum WE;Sheu SS Crosstalk signaling between mitochondrial Ca2+and ROS 2009

27.Yamashima T;Oikawa S The role of lysosomal rupture in neuronal death 2009(04)

28.Li Y;Yang X;Ma C;Qiao J Zhang C Necroptosis con-tributes to the NMDA-induced excitotoxicity in rat's cul-tured cortical neurons 2008(2-3)

29.Wu W;Liu P;Li J Necroptosis:an emerging form of programmed cell death 2012(03)

30.Maccarrone M;Melino G;Finazzi-Agrò A Lipoxy-genases and their involvement in programmed cell death 2001(08)

31.Bartke N;Hannun YA Bioactive sphingolipids:metabol-ism and function 2009

32.Liu B;Xu N;Man Y;Shen H Avital I Stojadinovic A Liao DJ Apoptosis in living animals is assisted by sca-venger cells and thus may not mainly go through the Cy-tochrome C-Caspase pathway 2013(09)

33.Kaczmarek A;Vandenabeele P;Krysko DV Necroptosis:the release of damage-associated molecular patterns and its physiological relevance 2013(02)

34.Tsai SY;Segovia JA;Chang TH;Morris IR Berton MT Tessier PA Tardif MR Cesaro A Bose S DAMP mo-lecule S100A9 acts as a molecular pattern to enhance inflammation during influenza a virus infection:role of DDX21-TRIF-TLR4-MyD88 pathway 2014(01)

35.Long JS;Ryan KM New frontiers in promoting tumour cell death:targeting apoptosis,necroptosis and autophagy 2012(49)

引证文献(2条)

1.劳晓洁,郑志军,卢伟,陈永峰TNF-α介导骨髓细胞死亡及其在再障发病中的作用[期刊论文]-台州学院学报 2014(06)

2.郑彦涛,刘斌,Robert Lodato,李奇林,蓝迪慧,洪小英,鲜华羊膜细胞可保护和修复缺血再灌注损伤小鼠脑组织细胞[期刊论文]-中国组织工程研究 2014(37)

引用本文格式：巴微.逄越.李庆伟.Wei Ba.Yue Pang.Qingwei Li程序性坏死（Necroptosis）的分子机制[期刊论文]-遗传2014(6)