Trends in Biochemical Sciences
ReviewThe molecular regulation of programmed necrotic cell injury
Section snippets
No accident: necrotic cell death is a programmed event
The balance between cellular proliferation and cell death is critical for homeostasis of higher organisms. Pathologists have long relied on morphology to distinguish different forms of cell death. The advent of molecular biology greatly enhanced our knowledge of the biochemical regulation of apoptosis. By comparison, our understanding of the biochemical pathways that regulate non-apoptotic cell death programs such as necrosis remained scarce. Until recently, the prevalent view was that cellular
Crosstalk between apoptosis and programmed necrosis
It is now clear that signaling by TNF-like death cytokines can result in at least one of three outcomes: nuclear factor kappa-B (NF-κB) activation, apoptosis or programmed necrosis. Evidence indicates that the activation of one response often opposes the others. For example, under most circumstances, TNF stimulation results in NF-κB activation rather than cell death. However, when NF-κB activation is inhibited, either by macromolecular synthesis inhibitors, or by expression of a dominant
RIP1: a pleiotropic kinase controlling cell survival and cell death signals
A breakthrough in the study of programmed necrosis came when several groups described that the serine/threonine kinase RIP1 plays an obligate role in mediating programmed necrotic cell death induced by FasL, TNF, TRAIL (TNF-related apoptosis-inducing ligand), and the combination of interferon and double stranded RNA 9, 12, 13, 14. Early studies indicated that RIP1 plays an obligate role in the activation of NF-κB (reviewed in 15, 16). For example, Abelson-transformed Rip1−/− pre-B cells were
A RIP1–RIP3 pro-necrotic complex regulates programmed necrosis
The fact that RIP1 activates signaling pathways other than programmed necrosis suggests that additional mechanisms must exist to specifically regulate or mediate its pro-necrotic function. Recently, two separate RNA interference (RNAi) screens identified another RIP family kinase, RIP3, as an essential mediator for TNF-, FasL- and TRAIL-mediated programmed necrosis 27, 28. Rip3−/− primary MEFs respond normally to TNF-induced apoptosis and NF-κB activation, but are resistant to programmed
The role of FADD and caspases: friend or foe?
Caspase inhibition has been observed in malignant diseases and during certain viral infections 9, 46. Under these conditions, TNF-like cytokines might preferentially induce programmed necrosis. However, it is important to remember that programmed necrosis can proceed in the absence of caspase inhibition. For instance, in Jurkat cells expressing both TNFR1 and TNFR2, TNF stimulation alone is sufficient to induce RIP1 and RIP3 recruitment to the caspase 8 associated complex and programmed
Does protein ubiquitylation regulate programmed necrosis?
Protein ubiquitylation is an important process that regulates numerous signal transduction pathways. Many proteins in the TNF signaling pathway are targets of ubiquitylation. For instance, TNFR1-bound RIP1 is modified heavily through K63-specific polyubiquitylation, although more recent results indicate that RIP1 can also undergo non-K63-mediated ubiquitylation [49]. Polyubiquitylated RIP1 mediates activation of the pro-survival transcription factor NF-κB by binding NEMO, the regulatory subunit
Effector mechanisms of programmed necrosis
Although it is clear that caspase-mediated cleavage of cellular proteins causes apoptotic death, much less is known about the mechanisms by which programmed necrosis kills cells. The most remarkable morphological feature of programmed necrosis is the organelle and cell swelling that culminates in rupture of the plasma membrane. The increase in cell volume and extensive intracellular vacuole formation implies an imbalance in osmotic pressure. Although the details remain fuzzy, the prevailing
Concluding remarks
Recent studies have defined a RIP1–RIP3 kinase complex that regulates death cytokine-induced programmed necrosis. Rip3−/− mice have provided a valuable model to examine the role of programmed necrosis in anti-viral inflammatory responses. RIP1/RIP3-dependent programmed necrosis might be important in other inflammatory diseases including drug-induced tissue inflammation, auto-inflammatory diseases and cancers. Indeed, RIP3 is required for cerulein-induced pancreatitis 28, 29. Drugs that target
Acknowledgement
The authors would like to thank Tia Bumpus for critical reading of the manuscript. DM is supported by a NIH pre-doctoral training grant (T32 AI07349). F.K-M. Chan is a member of the UMass DERC (DK32520).
References (70)
Necrosis, a well-orchestrated form of cell demise: signalling cascades, important mediators and concomitant immune response
Biochim. Biophys. Acta
(2006)A role for tumor necrosis factor receptor-2 and receptor-interacting protein in programmed necrosis and antiviral responses
J. Biol. Chem.
(2003)Tumor necrosis factor-induced nonapoptotic cell death requires receptor-interacting protein-mediated cellular reactive oxygen species accumulation
J. Biol. Chem.
(2004)- et al.
The RIP kinases: crucial integrators of cellular stress
Trends Biochem. Sci.
(2005) Activation of IKK by TNFα requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO
Mol. Cell
(2006)Ubiquitination of RIP is required for tumor necrosis factor alpha-induced NF-κB activation
J. Biol. Chem.
(2006)IAP antagonists target cIAP1 to induce TNFα-dependent apoptosis
Cell
(2007)IAP antagonists induce autoubiquitination of c-IAPs, NF-κB activation, and TNFalpha-dependent apoptosis
Cell
(2007)TNF-α induces two distinct caspase-8 activation pathways
Cell
(2008)Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation
Cell
(2009)
Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-α
Cell
Cleavage of RIP3 inactivates its caspase-independent apoptosis pathway by removal of kinase domain
Cell Signal
Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes
Cell
Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway
Cell
Identification of a novel homotypic interaction motif required for the phosphorylation of receptor-interacting protein (RIP) by RIP3
J. Biol. Chem.
Cytomegalovirus M45 cell death suppression requires receptor-interacting protein (RIP) homotypic interaction motif (RHIM)-dependent interaction with RIP1
J. Biol. Chem.
Drosophila immune deficiency (IMD) is a death domain protein that activates antibacterial defense and can promote apoptosis
Developmental cell
Rip1 mediates the Trif-dependent toll-like receptor 3- and 4-induced NF-κB activation but does not contribute to interferon regulatory factor 3 activation
J. Biol. Chem.
Toll-like receptor 3 and STAT-1 contribute to double-stranded RNA+ interferon-gamma-induced apoptosis in primary pancreatic beta-cells
J. Biol. Chem.
Cytomegalovirus M45 cell death suppression requires RHIM-dependent interaction with receptor-interacting protein 1 (RIP1)
J. Biol. Chem.
A ubiquitin replacement strategy in human cells reveals distinct mechanisms of IKK activation by TNFα and IL-1β
Mol. Cell
Ubiquitination of RIP1 regulates an NF-kappaB-independent cell-death switch in TNF signaling
Curr. Biol.
Regulation of early wave of germ cell apoptosis and spermatogenesis by deubiquitinating enzyme CYLD
Dev. cell
Reactive oxygen species regulate activation-induced T cell apoptosis
Immunity
Cytotoxic activity of tumor necrosis factor is mediated by early damage of mitochondrial functions. Evidence for the involvement of mitochondrial radical generation
J. Biol. Chem.
The RIP-like kinase, RIP3, induces apoptosis and NF-κB nuclear translocation and localizes to mitochondria
FEBS Lett.
TNF-induced activation of the Nox1 NADPH oxidase and its role in the induction of necrotic cell death
Mol. Cell
The CD95 type I/type II model
Semin. Immunol.
Identification of RIP1 kinase as a specific cellular target of necrostatins
Nat. Chem. Biol.
Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury
Nat. Chem. Biol.
The p53-cathepsin axis cooperates with ROS to activate programmed necrotic death upon DNA damage
Proc. Natl. Acad. Sci. U. S. A.
Linking JNK signaling to NF-κB: a key to survival
J. Cell Sci.
An endotoxin-induced serum factor that causes necrosis of tumors
Proc. Natl. Acad. Sci. U. S. A.
Caspase-independent cell killing by Fas-associated protein with death domain
J. Cell Biology
Differential signaling to apoptotic and necrotic cell death by Fas-associated death domain protein FADD
J. Biol. Chem.
Cited by (127)
Novel, non-conventional pathways of necroptosis in the heart and other organs: Molecular mechanisms, regulation and inter-organelle interplay
2023, Biochimica et Biophysica Acta - Molecular Cell ResearchProtein kinase D: A therapeutic target in experimental alcoholic pancreatitis
2022, Biochimica et Biophysica Acta - Molecular Basis of DiseaseThe effects of aspartame on the HTR8/SVneo extravillous trophoblast cell line
2022, Reproductive BiologyRole of necroptosis in traumatic brain and spinal cord injuries
2022, Journal of Advanced ResearchNecroptosis in heart disease: Molecular mechanisms and therapeutic implications
2022, Journal of Molecular and Cellular Cardiology