RIP1/RIP3-regulated necroptosis as a target for multifaceted disease therapy (Review)

  1. TNFR1-mediated signal transduction, which can propel cell survival, apoptosis and necroptosis
  2. Different modifications of RIP1 can induce distinct outcomes of cell survival, apoptosis and necroptosis.
  3. Following binding of TNF-α to TNFR1 at the plasma membrane,
  4. TNF-receptor-associated death domain (TRADD) recruits downstream proteins, namely RIP1, the E3 ubiquitin ligases TNF-receptor-associated factor (TRAF) 2, TRAF5, and the cellular inhibitor of apoptosis (cIAP) 1 and cIAP2, to form the complex I.
  5. Then, the complex I mediates NF-κB and MAPK signaling,
  6. contributing to cell survival or other non-death functions.
  7. The K63-linked ubiquitination of RIP1 by cIAP1/2 promotes both the formation and activation of the transforming growth factor-activated kinase 1 (TAK1)-binding protein (TAB) complex and the inhibitor of NF-κB kinase (IKK) complex (consisting of NF-κB essential modulator, IKKα and IKKβ), supporting the NF-κB pathway activation, and ultimately leading to cell survival.

文章でカスケードを説明するのは難しいことだと思いますが、上で紹介した例文はわかりやすいと思いました。NF-κBを介してcell survivalを実現しますと言い切ったあとで、そのシグナリングの詳細を付け足しています。ここまで役者が多いと、文章の行先を先に示すのは効果的だと思いました。


Impaired RIPK1 ubiquitination sensitizes mice to TNF toxicity and inflammatory cell death 30 September 2020

  1. TNFR1 (TNF receptor 1) trimerization induced by TNF binding
  2. results in recruitment of TRAF2 (TNF receptor-associated factor 2), TRADD (TNF receptor type 1 associated death domain protein), RIPK1 and c-IAP1 and 2 (cellular inhibitor of apoptosis 1 and 2).
  3. The E3 ligases c-IAP1/2 then ubiquitinate several proteins in the complex, including themselves and RIPK1, with K11-, K48- and K63-linked chains.
  4. K63-linked ubiquitin chains conjugated on c-IAP1/2 enable the binding of LUBAC (linear ubiquitin chain assembly complex),
  5. which subsequently adds linear ubiquitin chains .
  6. NEMO (NF-kappa-B essential modulator) binds to linear chains,
  7. which enables recruitment of IKKα/β (inhibitor of nuclear factor kappa-B kinaseα/β)
  8. and NF-κB activation.
  9. K63-linked ubiquitin-binding proteins TAB2/3 (TAK1-binding proteins 2 and 3) bring TAK1 (transforming growth factor beta-activated kinase 1) to the complex,
  10. which also contributes to activation of NF-κB and MAPK signaling.



Necroptosis: A new way of dying? Cancer Biol Ther. 2016; 17(9): 899–910. Published online 2016 Jul 19. doi: 10.1080/15384047.2016.1210732 PMCID: PMC5036404 PMID: 27434654

  1. The extrinsic portion can be activated by ligands binding their cell surface death receptors such as FASL binding FAS, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) binding death receptor 5 (DR5) or tumor necrosis factor-α (TNFα) binding TNF receptor 1 (TNFR1).
  2. FAS-associated death domain protein (FADD) is recruited to the FASL-FAS or TRAIL-DR5 receptor complex as well as to the cytosolic complex IIa for activation of Caspase-8 in the context of FLIP inhibition and loss of cellular inhibitors of apoptosis (cIAPs).
  3. TNFR1–associated death domain protein (TRADD), receptor-interacting protein kinase 1 (RIP1) and TNFR2-associated factor-2 (TRAF2) are recruited to TNFα-bound TNFR1 forming the pro-survival complex I as a prerequisite to apoptotic signaling via this death receptor.
  4. K-63 and M-1 linked poly-ubiquitination of RIP 1 by cIAPs and LUBAC respectively, antagonised by the second mitochondria-derived activator of caspases (SMAC) and cylandromatosis (CYLD), stabilises complex I formation.
  5. This allows binding of the NF-κB essential modifier (NEMO) and transforming growth factor β-activated protein kinase (TAK) binding protein (TAB) to associate with RIP1 via the ubiquitin chains
  6. thus activating NF-κB and cell survival signaling.
  7. Pro-survival genes such as opa1, c-iaps, traf2, a20 and c-flip are transcribed in the nucleus.



Controlled detonation: evolution of necroptosis in pathogen defense Michelle Brault, Andrew Oberst First published: 20 December 2016

  1. In most cellular contexts, TNF is a pro-survival signal.
  2. Upon engagement, its receptor interacts with numerous cytosolic proteins including RIPK1, forming a receptor-associated complex that triggers NF-κB activation.
  3. Subsequently, it is thought that RIPK1 can translocate to the cytosol, where it forms additional complexes.
  4. One of these is a complex that contains RIPK3, the so-called necrosome.
  5. Formation of this complex requires the interaction of the RIP homotypic interaction motif (RHIM) domains present in both RIPK1 and RIPK3
  6. and can lead to RIPK3 activation
  7. and cell death,
  8. but is normally prevented from doing so
  9. by the action of a heterodimeric enzyme complex composed of caspase-8 and cFLIP.
  10. These enzymes are recruited to RIPK1 via the adapter FADD and cooperate with E3 ubiquitin ligases, the IAPs, to abrogate necrosome formation and prevent necroptosis.