The molecular regulation of programmed necrotic cell injury

doi:10.1016/j.tibs.2010.03.001

Trends in Biochemical Sciences

Volume 35, Issue 8, August 2010, Pages 434-441

https://doi.org/10.1016/j.tibs.2010.03.001 Get rights and content

Proper regulation of cell death is essential for metazoan development and functions. Unlike apoptosis, necrosis is a more inflammatory form of cell death that might contribute to antiviral immunity. Indeed, necrotic cell injury is distinguished from apoptosis by extensive organelle and cell swelling and plasma membrane rupture. Recent evidence indicates that an elaborate biochemical network emanating from receptors in the TNF superfamily can induce apoptosis as well as necrotic cell death. The induction of necrosis by TNF-like cytokines requires biochemical components that are distinct from those involved in apoptosis. Specifically, serine/threonine protein kinases in the receptor interacting protein (RIP) family are required for “programmed” necrotic cell injury. In this review, we discuss the molecular crosstalk between apoptosis and programmed necrosis, with a special emphasis on how caspases, protein ubiquitylation and phosphorylation regulate the induction of 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).

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Trends in Biochemical Sciences

ReviewThe molecular regulation of programmed necrotic cell injury

Section snippets

No accident: necrotic cell death is a programmed event

Crosstalk between apoptosis and programmed necrosis

RIP1: a pleiotropic kinase controlling cell survival and cell death signals

A RIP1–RIP3 pro-necrotic complex regulates programmed necrosis

The role of FADD and caspases: friend or foe?

Does protein ubiquitylation regulate programmed necrosis?

Effector mechanisms of programmed necrosis

Concluding remarks

Acknowledgement

Biochim. Biophys. Acta

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J. Biol. Chem.

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Cell Signal

Cell

Cell

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J. Biol. Chem.

Developmental cell

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Mol. Cell

Curr. Biol.

Dev. cell

Immunity

J. Biol. Chem.

FEBS Lett.

Mol. Cell

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.

Review
The molecular regulation of programmed necrotic cell injury