Necroptosis

The Necroptosis Signaling Pathway

Necroptosis is a programmed form of necrosis, or inflammatory cell death.[1] Conventionally, necrosis is associated with unprogrammed cell death resulting from cellular damage or infiltration by pathogens, in contrast to orderly, programmed cell death via apoptosis. The discovery of necroptosis showed that cells can execute necrosis in a programmed fashion and that apoptosis is not always the preferred form of cell death. Furthermore, the immunogenic nature of necroptosis favors its participation in certain circumstances, such as aiding in defence against pathogens by the immune system. Necroptosis is well defined as a viral defense mechanism, allowing the cell to undergo "cellular suicide" in a caspase-independent fashion in the presence of viral caspase inhibitors to restrict virus replication.[2] In addition to being a response to disease, necroptosis has also been characterized as a component of inflammatory diseases such as Crohn's disease, pancreatitis, and myocardial infarction.[3][4]

The signaling pathway responsible for carrying out necroptosis is generally understood. TNFα leads to stimulation of its receptor TNFR1. TNFR1 binding protein TNFR-associated death protein TRADD and TNF receptor-associated factor 2 TRAF2 signals to RIPK1 which recruits RIPK3 forming the necrosome also named ripoptosome.[2] Phosphorylation of MLKL by the ripoptosome drives oligomerization of MLKL, allowing MLKL to insert into and permeabilize plasma membranes and organelles.[5][6] Integration of MLKL leads to the inflammatory phenotype and release of damage-associated molecular patterns (DAMPs), which elicit immune responses.

  1. ^ Nirmala JG, Lopus M (April 2020). "Cell death mechanisms in eukaryotes". Cell Biology and Toxicology. 36 (2): 145–164. doi:10.1007/s10565-019-09496-2. PMID 31820165. S2CID 208869679.
  2. ^ a b Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, Walczak H, Vandenabeele P (February 2014). "Regulated necrosis: the expanding network of non-apoptotic cell death pathways". Nature Reviews. Molecular Cell Biology. 15 (2): 135–47. doi:10.1038/nrm3737. PMID 24452471. S2CID 13919892.
  3. ^ Günther C, Martini E, Wittkopf N, Amann K, Weigmann B, Neumann H, Waldner MJ, Hedrick SM, Tenzer S, Neurath MF, Becker C (September 2011). "Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis". Nature. 477 (7364): 335–9. Bibcode:2011Natur.477..335G. doi:10.1038/nature10400. PMC 3373730. PMID 21921917.
  4. ^ Linkermann A, Green DR (January 2014). "Necroptosis". The New England Journal of Medicine. 370 (5): 455–65. doi:10.1056/nejmra1310050. PMC 4035222. PMID 24476434.
  5. ^ Wang H, Sun L, Su L, Rizo J, Liu L, Wang LF, Wang FS, Wang X (April 2014). "Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3". Molecular Cell. 54 (1): 133–146. doi:10.1016/j.molcel.2014.03.003. PMID 24703947.
  6. ^ Su L, Quade B, Wang H, Sun L, Wang X, Rizo J (October 2014). "A plug release mechanism for membrane permeation by MLKL". Structure. 22 (10): 1489–500. doi:10.1016/j.str.2014.07.014. PMC 4192069. PMID 25220470.