- TNFR1-mediated signal transduction, which can propel cell survival, apoptosis and necroptosis
- Different modifications of RIP1 can induce distinct outcomes of cell survival, apoptosis and necroptosis.
- Following binding of TNF-α to TNFR1 at the plasma membrane,
- 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.
- Then, the complex I mediates NF-κB and MAPK signaling,
- contributing to cell survival or other non-death functions.
- 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.
- TNFR1 (TNF receptor 1) trimerization induced by TNF binding
- 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).
- The E3 ligases c-IAP1/2 then ubiquitinate several proteins in the complex, including themselves and RIPK1, with K11-, K48- and K63-linked chains.
- K63-linked ubiquitin chains conjugated on c-IAP1/2 enable the binding of LUBAC (linear ubiquitin chain assembly complex),
- which subsequently adds linear ubiquitin chains .
- NEMO (NF-kappa-B essential modulator) binds to linear chains,
- which enables recruitment of IKKα/β (inhibitor of nuclear factor kappa-B kinaseα/β)
- and NF-κB activation.
- 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,
- 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
- 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).
- 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).
- 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.
- 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.
- 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
- thus activating NF-κB and cell survival signaling.
- 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
- In most cellular contexts, TNF is a pro-survival signal.
- Upon engagement, its receptor interacts with numerous cytosolic proteins including RIPK1, forming a receptor-associated complex that triggers NF-κB activation.
- Subsequently, it is thought that RIPK1 can translocate to the cytosol, where it forms additional complexes.
- One of these is a complex that contains RIPK3, the so-called necrosome.
- Formation of this complex requires the interaction of the RIP homotypic interaction motif (RHIM) domains present in both RIPK1 and RIPK3
- and can lead to RIPK3 activation
- and cell death,
- but is normally prevented from doing so
- by the action of a heterodimeric enzyme complex composed of caspase-8 and cFLIP.
- 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.