Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2014 Jan 30;370(5):455-65.
doi: 10.1056/NEJMra1310050.

Necroptosis

Andreas Linkermann  1 , Douglas R Green
Affiliations
Free PMC article
Review

Necroptosis

Andreas Linkermann et al. N Engl J Med. .
Free PMC article
No abstract available

PubMed Disclaimer

Figures

Figure 1
Figure 1. Programmed cell death is mediated by apoptosis or regulated necrosis
The term programmed cell death was widely used synonymously with apoptosis until necrotic cell death was demonstrated to depend on genetically defined signaling pathways. Whereas the role of caspase-mediated apoptosis in diseases has been revealed in detail over the last three decades, the contribution of regulated necrosis to the pathophysiology of diseases was investigated only recently. Pathways of regulated necrosis include necroptosis, dependent on RIPK3, and regulated necrosis mediated by mitochondrial permeability transition (MPT) which involves cyclophilin D-dependent opening of the mitochondrial permeability transition pore. Whereas MPT and necroptosis have been demonstrated to represent two distinct pathways, other emerging signaling cascades of regulated necrosis have been described, but it remains currently unclear to what extent such pathways may have overlapping mechanisms.
Figure 2
Figure 2. Activators of the necrosome as therapeutic targets
Various stimuli lead to the activation of the supramolecular necroptosis-inducing complex, referred to as the necrosome. Initially, studies of necroptosis employed models of death receptor stimulation in the presence of caspase-inhibition (not shown). The intracellular adapter molecules FADD and TRADD recruit RIPK1, which subsequently undergoes an incompletely understood series of ubiquitylation, deubiquitinylation, and phosphorylation events before exposing its rip homotypic interaction motif (RHIM-domain) to recruit RIPK3. RIPK1, RIPK3 and MLKL are phosphorylated during the assembly of the necrosome. Within the human genome, RIPK1, RIPK3 and two other proteins exhibit RHIM-domains. One of these is TRIF, an intracellular signal transducer that is capable of activating the necrosome downstream of Toll-like receptors which are triggered by microbial molecules. The fourth RHIM-domain protein, DAI, integrates signals from viral RNA sensors into the necrosome. Finally, viral infection is accompanied by production of interferon, which triggers the JAK/STAT-dependent de novo synthesis of protein kinase R (PKR) which phosphorylates FADD to directly interact with RIPK1 and induce necrosome formation. Death receptor-mediated necroptosis involves deubiquitinylation of RIPK1, the kinase domain of which is targeted by necrostatin-1 (Nec-1). Second generation RIP1-kinase inhibitors, such as Nec-1s, a stable version of Nec-1 which is more potent at lower concentrations, might reduce observed side effects. Necrosulfonamide (NSA) inhibits MLKL and prevents the activity of the necrosome in human cells. In addition, RIPK3-inhibitors, death receptor antagonists or plasma membrane channel blockers might be attractive therapeutical targets.
Figure 3
Figure 3. Combination therapy to target regulated necrosis
In ischemia-reperfusion injury, independent pathways of regulated necrosis contribute additively to overall organ damage. Whereas formation of the necroptotic pathway involves RIPK1-triggered assembly of the necrosome (MLKL-RIPK3), mitochondrial permeability transition (MPT) independently contributes in a cyclophilin D dependent manner. Necroptosis may be blocked by necrostatin-1 (Nec-1), second generation “stable” Nec-1 (Nec-1s) or the MLKL-inhibitor necrosulfonamide (NSA). MPT is inhibited by cyclosporine A (CsA) or sanglifehrin A (SfA). Combination therapy with Nec-1 and SfA exhibited significantly stronger protection compared to each monotherapy.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Cho YS, Challa S, Moquin D, et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell. 2009;137(6):1112–1123. - PMC - PubMed
    1. He S, Wang L, Miao L, et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell. 2009;137(6):1100–1111. - PubMed
    1. Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol. 2010;11(10):700–714. - PubMed
    1. Zhang DW, Shao J, Lin J, et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science. 2009;325(5938):332–336. - PubMed
    1. Galluzzi L, Vitale I, Abrams JM, et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ. 2011;19(1):107–20. - PMC - PubMed