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Necrotic Cell Death Signaling Interactive Pathway

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Pathway Description:

Necrosis has been classically defined as an unprogrammed form of cell death that occurs in response to overwhelming chemical or physical insult. Typical endpoints of necrosis include the swelling and rupture of necrotic cells.

While it was previously thought that necrosis was passive and unprogrammed, recent data have uncovered a caspase-independent process that resembles necrosis. Induction of this programmed form of necrosis, termed necroptosis, can occur from extracellular signals (death receptor-ligand binding) or intracellular cues (microbial nucleic acids) and is actively inhibited by caspase activity. In addition, another type of programmed necrosis is called pyroptosis. This form of cell death is a significant player in the innate immune response and is mediated by inflammatory caspases.

Necroptosis

RIPK1, RIPK3, and MLKL are the major molecules involved in necroptosis. The kinase activity of RIPK1 is crucial to multiple complexes capable of regulating inflammation (complex I), apoptosis (complex IIa), and necroptosis (complex IIb). Ubiquitination of RIPK1 by IAPs leads to activation of NF-B and subsequent inflammatory cascade, and phosphorylation of RIPK1 at Ser320. Inhibition of complex I, by de-ubiquitinating enzymes like CYLD and A20, drives RIPK1 toward interactions with caspase-8 and death-inducing complex IIa pathways. Interaction with RIPK3 is required for complex IIb signaling and necroptosis. Caspase-8 activity can inhibit necroptosis through cleavage of RIPK1 and RIPK3. Inhibition of caspase-8 activity by FLIP, a catalytically inactive homolog of caspase 8 that can incorporate into complex II, can prevent RIPK1 cleavage and drive necroptosis. Inhibition of necroptosis has been observed in the presence of necrostatin-1 (Nec-1), a small molecule that has been reported to prevent RIP1K activity. RIPK1 also has autophosphorylation sites, including Ser166, Ser161, and Ser14/15, that are inhibited by Nec1.

During necroptosis, RIPK3 is phosphorylated at Ser227, which is required for activation of MLKL, an effector protein that acts downstream of RIPK1 and RIPK3. These activities are part of complex IIb, also called the necrosome. Phosphorylation of MLKL induces oligomerization and translocation of MLKL to the plasma membrane to interact with phosphatidylinositides, inducing membrane permeabilization and cell destruction. MLKL-induced permeabilization of the plasma membrane leads to influx of Ca2+ or Na+ ions and direct pore formation with the release of cell damage-associated molecular patterns (cDAMPs), such as mitochondrial DNA (mtDNA), high-mobility group box 1 (HMGB1), interleukin (IL)-33, IL-1α, and ATP. These effects appear to be independent of ROS production, even though in some cases cellular ROS seems to accompany necroptosis.

Oligomerized RIPK3 can induce apoptosis when MLKL is absent, even without RIPK1 activity (RIPK1-independent necroptosis). Additionally, stabilization of the necrosome in the absence of a functional RIPK1-MLKL interaction can recruit caspase 8 and trigger apoptosis (RIPK1-independent apoptosis). Importantly, the interaction between RIPK1 and RIP3K is not linear. RIPK1 can suppress both caspase 8-dependent apoptosis and RIPK3-driven necroptosis, but under certain conditions RIPK1 can also act to activate RIPK3.

Toll-like receptors (TLRs) activate necroptosis through TRIF interaction with the necrosome. Independent of RIPK1, RIPK3 can also be engaged directly by TRIF or interferon signaling to induce necroptosis by activation by DAI/ZBP1, which are sensors of viral infection. Furthermore, a RIPK-independent inflammatory response without infection can be induced by necroptosis through activation by DAMPs.

Current research suggests that necroptosis plays a major role in cancer as well as several neurodegenerative diseases. It is thought that necroptosis is involved in metastasis; therefore, inhibition of the necroptotic pathway could limit tumor growth. In addition, it has been reported that treatment with Necrostatin-1 improved cell viability in Alzheimer’s and Parkinson’s diseases. Taken together, investigation of the mechanisms of necroptosis and other cell death pathways may provide therapeutic insights for the development of novel treatments for a variety of diseases.

Pyroptosis

The sequence of events during pyroptosis includes binding of pathogenic molecules, pore formation in, and rupture of, the plasma membrane, and the extracellular release of inflammatory substances from the cytoplasm. Stimulators of pyroptosis include pathogen-associated pattern molecules (PAMPs) and danger-associated pattern molecules (DAMPs) to particular pattern recognition receptors (PRRs) such as toll-like receptors (TLRs).

There are generally 4 components to an inflammasome complex: a cytosolic PRR; a nucleotide-binding domain and leucine-rich-repeat (NLR) or AIM2-like receptor (ALR) family member, an adaptor protein (ASC), and pro-caspase-1. Priming and activation are the 2 steps required for induction of pyroptosis. After inflammasome assembly, pro-caspase-1 is proteolyically activated and cleaves the cytokines pro-IL1β and pro-IL18 to their mature, pro-inflammatory forms, IL1β and IL18, as well as inducing cleavage of gasdermin D (GSDMD). Intracellular cytosolic LPS induces noncanonical pyroptosis leading to cleavage of GSDMD by active caspase 4*, 5*, and/or 11. The cleavage of GSDMD plays a role in both canonical and noncanonical activation of pyroptosis and, therefore, GSDMD is a critical molecular mediator. It has recently been demonstrated that cleavage of GSDMD at the C-terminal doman results in pore formation in the plasma membrane by the activated N-terminal via direct or indirect activation of IL-1β.

Research into the therapeutic possibilities of targeting pyroptosis suggests benefits to cancer, autoimmune and neurodegenerative diseases, as well as other pathological conditions. The potential for pyroptosis to mediate cancer is evidenced by research demonstrating that omega-3 fatty acids activate pyroptosis in triple negative breast cancer cells; however, the mechanism remains to be elucidated. In inflammatory bowel disease, activation of the inflammasome and caspase induction is indicative of pyroptosis, and this may also be a promising direction of research to develop novel therapeutics.

*NB: caspase-4 and caspase-5 are the human homologs of murine caspase-11.

Selected Reviews:

created March 2019
  • KinaseKinase
  • PhosphatasePhosphatase
  • Transcription FactorTranscription Factor
  • CaspaseCaspase
  • ReceptorReceptor
  • EnzymeEnzyme
  • pro-apoptoticpro-apoptotic
  • pro-survivalpro-survival
  • GAP/GEFGAP/GEF
  • GTPaseGTPase
  • G-proteinG-protein
  • AcetylaseAcetylase
  • DeacetylaseDeacetylase
  • Ribosomal subunitRibosomal subunit
  • Direct Stimulatory ModificationDirect Stimulatory Modification
  • Direct Inhibitory ModificationDirect Inhibitory Modification
  • Multistep Stimulatory ModificationMultistep Stimulatory Modification
  • Multistep Inhibitory ModificationMultistep Inhibitory Modification
  • Tentative Stimulatory ModificationTentative Stimulatory Modification
  • Tentative Inhibitory ModificationTentative Inhibitory Modification
  • Separation of Subunits or Cleavage ProductsSeparation of Subunits or Cleavage Products
  • Joining of SubunitsJoining of Subunits
  • TranslocationTranslocation
  • Transcriptional Stimulatory ModificationTranscriptional Stimulatory Modification
  • Transcriptional Inhibitory ModificationTranscriptional Inhibitory Modification
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