Death Receptor‐induced Necroptosis

Abstract

Recent studies on cellular in vitro models have made it clear that death receptor (DR)‐induced necrosis, also called necroptosis, is a programmed form of necrotic cell death. In contrast, accidental necrosis is mainly induced by physicochemical stress, such as heath or chemicals. Many DRs signal to apoptosis or necroptosis depending on whether caspases are active or not. The kinase activities of receptor‐interacting protein 1 (RIP1) and RIP3 have emerged as crucial regulators of DR‐induced necroptosis. The precise execution mechanisms during necroptosis are still poorly understood but involve different cellular compartments such as the mitochondria, the lysosomes and the cell membrane. In vivo, necroptosis occurs mainly in pathophysiological processes such as ischaemia‐reperfusion injury in heart, brain and kidneys, viral infection and pancreatitis, and is capable of killing tumour cells that have developed strategies to evade apoptosis. Thus, detailed knowledge of necroptotic signalling may be exploited in therapeutic strategies.

Key concepts:

  • Necrosis is characterized by swelling of the endoplasmic reticulum, mitochondria and cytoplasm, with subsequent rupture of the plasma membrane and lysis of the cells.

  • Death receptor‐induced necrosis, also called necroptosis, is a programmed form of necrotic cell death. This is in contrast to necrosis induced by physicochemical stress, such as heath or hydrogen peroxide.

  • The necrosis‐signalling complex, or necrosome, consists of a complex containing FADD, caspase‐8, RIP1 and RIP3.

  • Expression of RIP3 renders cells permissive to death receptor‐induced necroptosis.

  • RIP1 and RIP3 kinase activity is crucial for necroptotic signalling.

  • Apoptosis counteracts necrotic signalling by cleavage of RIP1 and RIP3.

  • Necroptosis forms a back‐up cell death mode in case caspases activity is prevented or inhibited.

  • In vivo, necroptosis occurs mainly in pathophysiological processes such as ischaemia‐reperfusion injury in heart, brain and kidneys, viral infection and pancreatitis, and is capable of killing tumour cells that have developed strategies to evade apoptosis.

Keywords: necrosis–death receptors; TNF‐necrosome; receptor‐interacting kinase; mitochondria‐reactive oxygen species; metabolism

Figure 1.

Cell morphology of apoptotic and necrotic cells by transmission electron microscopy. (a) Unstimulated L929sAhFas fibrosarcoma cell. The cell shows microvilli protruding from the entire surface (arrowhead), a smoothly outlined nucleus with chromatin in the form of heterochromatin and well‐preserved cytoplasmic organelles. (b) Apoptotic L929sAhFas cell (treated with agonistic anti‐Fas for 1 h) with condensed and marginated (arrowhead) chromatin. Note the nucleolus (n) and damaged mitochondria (arrow). (c) Necrotic L929sAhFas cell (treated with TNF for 7 h) with clumps of chromatin with ill‐defined edges, swollen and completely disrupted mitochondria (arrow) and loss of plasma membrane integrity (arrowhead). Scale bars: 1 μm, N, nucleus. Pictures are courtesy of Katharina D'Herde and Dmitri Krysko (Ghent University).

Figure 2.

The necrosome, a new player in death receptor‐induced necroptosis. (a) Schematic representation of the different domains in human RIP1 and RIP3. We indicated the number of amino acids corresponding to each domain, the modifications important for NFκB activation (K63‐linked polyubiquitin chains on K377 in RIP1) or necroptosis (phosphorylation on RIP1S161 and RIP3 S199). The interaction between RIP1 and RIP3 is mediated by the RHIM domain. Abbreviations: KD, kinase domain; RHIM, RIP homotypic interaction motif; DD, death domain. (b) TNF‐induced necroptosis signalling complexes. Upon TNFR1 stimulation, TRADD provides, by binding RIP1, TRAF2 and cIAP1 and cIAP2, a scaffold for the assembly of complex I at the plasma membrane. This complex is crucial for activating NFκB and MAPK pathways. K63‐linked polyubiquitination of RIP1 by cIAPs results in interaction of RIP1 with the TAK1 (TGF (transforming growth factor)‐β‐activated kinase 1)/TAB2 (TAK‐1 binding protein 2)/3 complex. K63‐linked TRAF2 polyubiquitination can also recruit the TAK1/TAB2/3 complex. TAK1 activates the IKK complex, containing IKK‐α, IKK‐β and NEMO/IKKγ, which in turn phosphorylates IκB and results in its K48 polyubiquitination and proteasomal degradation. Once freed from its inhibitor, NFκB translocates to the nucleus and induces transcription. In a negative feedback loop, NFκB‐mediated upregulation of A20 and CYLD targets RIP1 for K63 deubiquitination, thereby abolishing its ability to activate NFκB. After receptor internalization TRADD‐dependent secondary cytosolic complexes are formed (complex II). The establishment of complex II involves FADD‐mediated recruitment and activation of caspase‐8, leading to RIP1 and RIP3 cleavage. In conditions where apoptosis is blocked by experimental (e.g. zVAD) or physiological conditions (e.g. viral inhibitors), RIP1 and RIP3 assemble a complex involving FADD and caspase‐8. The asterisk indicates that TRADD may also be part of this complex; however, this has not been formally proven. Mutual direct or indirect phosphorylation of RIP1 and RIP3 in the necrosome activates necroptotic signalling. In addition, TNF induces the formation of a TNFR1 signalling complex containing TRADD, RIP1, Nox1/NOXA1 and the small GTPase Rac1. Recruitment of Nox1 complex to TNFR1 is dependent on the adaptor proteins TRADD and RIP1 kinase. Upon activation of Nox1, superoxide anions and consecutive hydrogen peroxides are generated eventually contributing to necroptosis. See text for details.

Figure 3.

Different intracellular signalling events contribute to necroptosis. The kinase activity of RIP1 is needed to induce necroptosis induced by death receptors and several other stimuli. Necrotic cell death depends on the kinase activity of RIP1, which is inhibitable by the compound Nec‐1, and on a phosphorylation loop between RIP1 and RIP3. The main players in the propagation of necroptosis are calcium and mitochondria. Calcium controls the activation of PLA2 and calpains, inducing lipid peroxidation (LOOH) and cathepsin release from lysosomes, respectively http://merops.sanger.ac.uk/. Mitochondria contribute to necroptosis by excessive ROS production, mitochondrial permeability transition (mPT) or ATP depletion. RIP3 mediates enhanced glycolysis through glycogenolysis, and glutaminolysis, stimulating Krebs cycle and ROS production. See text for details. In addition, Bcl‐2 family members also contribute to necroptotic signalling, probably by affecting the mitochondrial function.

close

References

Baines CP, Kaiser RA, Purcell NH et al. (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434: 658–662.

Baines CP (2009) The mitochondrial permeability transition pore and ischemia‐reperfusion injury. Journal of Molecular and Cellular Cardiology 46: 969–977.

Bertrand MJ, Milutinovic S, Dickson KM et al. (2008) cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Molecular Cell 30: 689–700.

Boya P and Kroemer G (2008) Lysosomal membrane permeabilization in cell death. Oncogene 27: 6434–6451.

Cauwels A, Janssen B, Waeytens A, Cuvelier C and Brouckaert P (2003) Caspase inhibition causes hyperacute tumor necrosis factor‐induced shock via oxidative stress and phospholipase A2. Nature Immunology 4: 387–393.

Chan FK (2000) The pre‐ligand binding assembly domain: a potential target of inhibition of tumour necrosis factor receptor function. Annals of the Rheumatic Diseases 59(suppl 1): i50–i53.

Ch'en IL, Beisner DR, Degterev A et al. (2008) Antigen‐mediated T cell expansion regulated by parallel pathways of death. Proceedings of the National Academy of Sciences of the United States of America 105: 17463–17468.

Cho YS, Challa S, Moquin D et al. (2009) Phosphorylation‐driven assembly of the RIP1‐RIP3 complex regulates programmed necrosis and virus‐induced inflammation. Cell 137: 1112–1123.

Degterev A, Hitomi J, Germscheid M et al. (2008) Identification of RIP1 kinase as a specific cellular target of necrostatins. Nature Chemical Biology 4: 313–321.

Degterev A, Huang Z, Boyce M et al. (2005) Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nature Chemical Biology 1: 112–119.

Doraiswamy PM and Finefrock AE (2004) Metals in our minds: therapeutic implications for neurodegenerative disorders. Lancet Neurology 3: 431–434.

Ermolaeva MA, Michallet MC, Papadopoulou N et al. (2008) Function of TRADD in tumor necrosis factor receptor 1 signaling and in TRIF‐dependent inflammatory responses. Nature Immunology 9: 1037–1046.

Feng S, Yang Y, Mei Y et al. (2007) Cleavage of RIP3 inactivates its caspase‐independent apoptosis pathway by removal of kinase domain. Cell Signal 19: 2056–2067.

Festjens N, Kalai M, Smet J et al. (2006a) Butylated hydroxyanisole is more than a reactive oxygen species scavenger. Cell Death and Differentiation 13: 166–169.

Festjens N, Vanden Berghe T and Vandenabeele P (2006b) Necrosis, a well‐orchestrated form of cell demise: signalling cascades, important mediators and concomitant immune response. Biochimica et Biophysica Acta 1757: 1371–1387.

Festjens N, Vanden Berghe T, Cornelis S and Vandenabeele P (2007) RIP1, a kinase on the crossroads of a cell's decision to live or die. Cell Death and Differentiation 14: 400–410.

Galluzzi L, Morselli E, Kepp O and Kroemer G (2009) Targeting post‐mitochondrial effectors of apoptosis for neuroprotection. Biochimica et Biophysica Acta 1787: 402–413.

Goossens V, Grooten J and Fiers W (1996) The oxidative metabolism of glutamine. A modulator of reactive oxygen intermediate‐mediated cytotoxicity of tumor necrosis factor in L929 fibrosarcoma cells. Journal of Biological Chemistry 271: 192–196.

Griffiths EJ and Rutter GA (2009) Mitochondrial calcium as a key regulator of mitochondrial ATP production in mammalian cells. Biochimica et Biophysica Acta 1787(11): 1324–1333.

He S, Wang L, Miao L et al. (2009) Receptor interacting protein kinase‐3 determines cellular necrotic response to TNF‐alpha. Cell 137: 1100–1111.

Hitomi J, Christofferson DE, Ng A et al. (2008) Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell 135: 1311–1323.

Holler N, Zaru R, Micheau O et al. (2000) Fas triggers an alternative, caspase‐8‐independent cell death pathway using the kinase RIP as effector molecule. Nature Immunology 1: 489–495.

Juhaszova M, Wang S, Zorov DB et al. (2008) The identity and regulation of the mitochondrial permeability transition pore: where the known meets the unknown. Annals of the New York Academy of Sciences 1123: 197–212.

Kelliher MA, Grimm S, Ishida Y et al. (1998) The death domain kinase RIP mediates the TNF‐induced NF‐kappaB signal. Immunity 8: 297–303.

Kerr JF, Wyllie AH and Currie AR (1972) Apoptosis: a basic biological phenomenon with wide‐ranging implications in tissue kinetics. British Journal of Cancer 26: 239–257.

Kim YS, Morgan MJ, Choksi S and Liu ZG (2007) TNF‐induced activation of the Nox1 NADPH oxidase and its role in the induction of necrotic cell death. Molecular Cell 26: 675–687.

Kroemer G, Galluzzi L, Vandenabeele P et al. (2009) Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death and Differentiation 16: 3–11.

Leist M, Single B, Castoldi AF, Kuhnle S and Nicotera P (1997) Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. Journal of Experimental Medicine 185: 1481–1486.

Li Y, Johnson N, Capano M, Edwards M and Crompton M (2004) Cyclophilin‐D promotes the mitochondrial permeability transition but has opposite effects on apoptosis and necrosis. Biochemical Journal 383: 101–109.

Lim SY, Davidson SM, Mocanu MM, Yellon DM and Smith CC (2007) The cardioprotective effect of necrostatin requires the cyclophilin‐D component of the mitochondrial permeability transition pore. Cardiovascular Drugs and Therapy 21: 467–469.

Lin Y, Choksi S, Shen HM et al. (2004) Tumor necrosis factor‐induced nonapoptotic cell death requires receptor‐interacting protein‐mediated cellular reactive oxygen species accumulation. Journal of Biological Chemistry 279: 10822–10828.

Mahoney DJ, Cheung HH, Mrad RL et al. (2008) Both cIAP1 and cIAP2 regulate TNFalpha‐mediated NF‐kappaB activation. Proceedings of the National Academy of Sciences of the USA 105: 11778–11783.

Meylan E and Tschopp J (2005) The RIP kinases: crucial integrators of cellular stress. Trends in Biochemical Sciences 30: 151–159.

Nakagawa T, Shimizu S, Watanabe T et al. (2005) Cyclophilin D‐dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434: 652–658.

Newton K, Sun X and Dixit VM (2004) Kinase RIP3 is dispensable for normal NF‐kappa Bs, signaling by the B‐cell and T‐cell receptors, tumor necrosis factor receptor 1, and Toll‐like receptors 2 and 4. Molecular and Cellular Biology 24: 1464–1469.

Odagiri K, Katoh H, Kawashima H et al. (2009) Local control of mitochondrial membrane potential, permeability transition pore and reactive oxygen species by calcium and calmodulin in rat ventricular myocytes. Journal of Molecular and Cellular Cardiology 46: 989–997.

Pobezinskaya YL, Kim YS, Choksi S et al. (2008) The function of TRADD in signaling through tumor necrosis factor receptor 1 and TRIF‐dependent Toll‐like receptors. Nature of Immunology 9: 1047–1054.

Schulze‐Osthoff K, Bakker AC, Vanhaesebroeck B et al. (1992) Cytotoxic activity of tumor necrosis factor is mediated by early damage of mitochondrial functions. Evidence for the involvement of mitochondrial radical generation. Journal of Biological Chemistry 267: 5317–5323.

Schutze S, Tchikov V and Schneider‐Brachert W (2008) Regulation of TNFR1 and CD95 signalling by receptor compartmentalization. Nature Reviews 9: 655–662.

Schweichel JU and Merker HJ (1973) The morphology of various types of cell death in prenatal tissues. Teratology 7: 253–266.

Smith CC, Davidson SM, Lim SY et al. (2007) Necrostatin: a potentially novel cardioprotective agent? Cardiovascular Drugs and Therapy 21: 227–233.

Sun H, Nikolovska‐Coleska Z, Yang CY et al. (2008) Design of small‐molecule peptidic and nonpeptidic Smac mimetics. Accounts of Chemical Research 41: 1264–1277.

Temkin V, Huang Q, Liu H, Osada H and Pope RM (2006) Inhibition of ADP/ATP exchange in receptor‐interacting protein‐mediated necrosis. Molecular and Cellular Biology 26: 2215–2225.

Vandenabeele P, Vanden Berghe T and Festjens N (2006) Caspase inhibitors promote alternative cell death pathways. Science's STKE 2006: pe44.

Vanlangenakker N, Berghe TV, Krysko DV, Festjens N and Vandenabeele P (2008) Molecular mechanisms and pathophysiology of necrotic cell death. Current Molecular Medicine 8: 207–220.

Varfolomeev E, Goncharov T, Fedorova AV et al. (2008) c‐IAP1 and c‐IAP2 are critical mediators of tumor necrosis factor alpha (TNFalpha)‐induced NF‐kappaB activation. Journal of Biological Chemistry 283: 24295–24299.

Vercammen D, Brouckaert G, Denecker G et al. (1998) Dual signaling of the Fas receptor: initiation of both apoptotic and necrotic cell death pathways. Journal of Experimental Medicine 188: 919–930.

Wang L, Du F and Wang X (2008) TNF‐alpha induces two distinct caspase‐8 activation pathways. Cell 133: 693–703.

Willingham SB, Bergstralh DT, O'Connor W et al. (2007) Microbial pathogen‐induced necrotic cell death mediated by the inflammasome components CIAS1/Cryopyrin/NLRP3 and ASC. Cell Host & Microbe 2: 147–159.

Wilson NS, Dixit V and Ashkenazi A (2009) Death receptor signal transducers: nodes of coordination in immune signaling networks. Nature Immunology 10: 348–355.

You Z, Savitz SI, Yang J et al. (2008) Necrostatin‐1 reduces histopathology and improves functional outcome after controlled cortical impact in mice. Journal of Cerebral Blood Flow and Metabolism 28: 1564–1573.

Zhang DW, Shao J, Lin J et al. (2009) RIP3, an energy metabolism regulator that switches TNF‐induced cell death from apoptosis to necrosis. Science 325: 332–336.

Further Reading

Degterev A and Yuan J (2008) Expansion and evolution of cell death programmes. Nature Reviews. Molecular Cell Biology 9: 378–390.

Galluzzi L and Kroemer G (2008) Necroptosis: a specialized pathway of programmed necrosis. Cell 135: 1161–1163.

Green DR, Ferguson T, Zitvogel L and Kroemer G (2009) Immunogenic and tolerogenic cell death. Nature Reviews 9: 353–363.

Zong WX and Thompson CB (2006) Necrotic death as a cell fate. Genes & Development 20: 1–15.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Declercq, Wim, Van Herreweghe, Franky, Berghe, Tom Vanden, and Vandenabeele, Peter(Dec 2009) Death Receptor‐induced Necroptosis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021566]