gocentral
commented
10 years ago Hi Aleks,
As discussed previously with you and David Hill, instead of adding a new term for 'necrosome', I have made this a synonym of 'ripoptosome' and I've edited the definition of 'ripoptosome' (and added a def. comment) to make this component more general. This arrangement mirrors better, I think, the current state of research. The term now reads:
[Term] id: GO:0097342 name: ripoptosome namespace: cellular_component def: "A protein complex whose core components are the receptor-interacting serine/threonine-protein kinases RIPK1 and RIPK3 (also called RIP1 and RIP3). Formation of the ripoptosome can induce an extrinsic apoptotic signaling pathway or a necroptotic signaling pathway. The composition of this protein complex may depend on several factors including nature of the signal, cell type and more." [GOC:mtg_apoptosis, PMID:22265414, PMID:22274400] comment: It has been shown that receptor-mediated necroptotic signaling pathway requires assembly of a ripoptosome protein complex consisting of caspase-8, caspase-10, Fas-associated death domain protein (FADD), casp8 and FADD-like apoptosis regulator (CFLAR) as well as the two receptor-interacting serine/threonine-protein kinases RIPK1 and RIPK3 (PMID:21737330). Optionally, depending on the receptor activated, this complex may contain TLR3 adaptor protein TRIF (PMID:21737330). synonym: "necrosome" RELATED [] synonym: "TNFR1 complex II" NARROW [PMID:22089168] synonym: "Tnfr1-CII" NARROW [PMID:22089168] is_a: GO:0043234 ! protein complex
Thanks again for your work, Paola
Original comment by: paolaroncaglia
Hello,
At the moment I am working on several papers describing necroptosis. A few paragraphs below contain a short introduction into the topic with the PMIDs of the publications used for annotations.
The process of necroptosis has been recently described as a type of programmed cell death distinct from apoptotic signaling pathway. It can be induced via activation of death receptors, death domain-containing members of the TNF receptor superfamily (PMID: 21876153) or Toll-like receptors (PMID:21737330) as well as oxidative stress or calcium overload (PMID: 22265414). It has been shown that receptor-mediated pathway requires an assembly of a ripoptosome protein complex which consists of caspase-8, caspase-10, Fas-associated death domain protein (FADD), casp8 and FADD-like apoptosis regulator (CFLAR) and two receptor-interacting serine/threonine-protein kinases RIPK1 and RIPK3 (PMID:21737330). Optionally, depending on the receptor activated this complex may contain TLR3 adaptor protein TRIF (PMID:21737330).
At the stage of ripoptosome assembly the decision has to be made whether the cell death undergoes apoptotic or necroptotic way (PMID: 21876153). Several factors play key roles in defining the further cell fate. In case if caspases 8 and 10 are functional which results in RIPK1 and RIPK3 cleavage, the cells will undergo apoptotic cell death. However, if the cleavage can be prevented either by using caspase-specific inhibitors or overexpressing caspase-resistant RIPKs, necroptotic process will be activated (PMID: 21876153). The following signaling pathway was shown to be dependent on RIPK kinase activity and, providing that RIPK1 kinase fails to phosphorylate the downstream targets, necroptosis cannot be executed. Upon blocking caspase activity RIPK1 and RIPK3 proteins form a complex called necrosome (PMID:22817896). Structural analysis of the functional signaling complex shows that it is represented by amyloid fibrils formed by RIPK1- and RIPK3-containing heterodimers. For the successful mediation of necroptotic pathway the mixed lineage kinase-like (MLKL) protein should be associated with this complex and phosphorylated by RIPK3 (PMID:22265413). Following that, necrosome binds to mitochondrial serine/threonine phosphatase PGAM5 which in its turn activates dynamin-1-like protein Drp1. Starting from this point the following events represent the execution phase of necroptosis involving mitochondria fission and plasma membrane disruption. Localized at outer mitochondrial membrane Drp1 upon desphosphorylation is able to be assembled into spiral complexes necessary to mediate membrane constriction (PMID: 21892144).
Interestingly, necrosome activity was shown to be involved only in necroptotic signaling pathway activated by extracellular stimuli, whereas intracelullar necroptosis inducers such as reactive oxygen species and calcium overload do not require RIPK kinase activity. On the contrary, they are able directly activate PGAM5 and thus control mitochondria fission (PMID:22265414).
According to that I would like to suggest several new terms for necroptotic process.
1.PMID: 22265414. The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways (2012). In this publication the authors identified PGAM5 as a convergent point of multiple programmed necrotic pathways. According to their data, specific inhibitors of RIP1 and RIP3 are able to attenuate the TNG-induced necroptosis, but human cells HeLa and HT-29 would still undergo necroptosis if it is induced by ROS generators or calcium ionophore treatment. However, all the tested necroptosis inducers appear not to cause a programmed necrotic cell death if PGAM5 was knocked down by siRNA or inhibited by a specific drug mdivi-1. These data lead to a conclusion that programmed necrotic cell death can be induced via (at least?) three different signaling pathways converging at the point where PGAM5 activates Drp1 responsible for mitochondria fission. Would it make sense to create an additional child term for GO:0060553 activation of necroptosis?
GO:0060555 activation of necroptosis by extracellular signals - already exists GO: activation of necroptosis by intracellular signals Possible definition:
Any process that activates necroptosis, a programmed form of necrotic cell death, as a result of a signal inside the cell, such as reactive oxygen species or elevated calcium concentration.
In order to be able to capture the information about specific intracellular necroptosis inducers, we may consider creating two children terms for GO: activation of necroptosis by intracellular signals activation of necroptosis by oxidative stress (reactive oxygen species) Possible definition:
A process that activates necroptosis, a programmed form of necrotic cell death, as a result of a signal inside the cell represented by reactive oxygen species.
activation of necroptosis by calcium overload Possible definition:
A process that activates necroptosis, a programmed form of necrotic cell death, as a result of a signal inside the cell represented by elevated calcium concentration.
2.PMID: 22265414 The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways (2012). 3.PMID: 22817896 The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis (2012). I would like to suggest to add a new term GO: necrosome defining a protein complex described in these publications. Possible definition: A protein complex formed by the association of RIP kinases RIPK1 and RIPK3, may contain MLKL and PGAM5. The formation of this complex is essential for the mediation of necroptosis, a programmed form of necrotic cell death, activated by extracellular signals involving death domain receptors and Toll-like receptors.
Many thanks, Aleks
Reported by: zebrafishembryo
Original Ticket: geneontology/ontology-requests/10447