Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions in a variety of cellular pathways related to both cell survival and death. In terms of cell death, RIPK1 plays a role in apoptosis and necroptosis. Some of the cell survival pathways RIPK1 participates in include NF-κB, Akt, and JNK.
RIPK1 is an enzyme that in humans is encoded by the RIPK1 gene, which is located on chromosome 6. This protein belongs to the Receptor Interacting Protein (RIP) kinases family, which consists of 7 members, RIPK1 being the first member of the family.
Structure
RIPK1 protein is composed of 671 amino acids, and has a molecular weight of about 76 kDa. It contains a serine/threonine kinase domain (KD) in the 300 aa N-Terminus, a death domain (DD) in the 112 aa C-Terminus, and a central region between the KD and DD called intermediate domain (ID). The kinase domain plays different roles in cell survival and is important in necroptosis induction. RIP interacts with TRAF2 via the kinase domain. The KD can also interact with Necrostatin-1, which is an allosteric inhibitor of RIPK1 kinase activity. Overexpression of RIP lacking kinase activity can activate NF-kB. The death domain is homologous to the DD of other receptors such as Fas, TRAILR2 (DR5), TNFR1 and TRAILR1 (DR4), so it can bind to these receptors, as well as TRADD and FADD in the TNFR1 signalling complex. Overexpression of RIP can induce apoptosis and can activate NF-kB, but overexpression of the RIP death domain can block NF-kB activation by TNF-R1. The intermediate domain is important for NF-kB activation and (RHIM)-dependent signalling. Via the intermediate domain, RIP can interact with TRAF2, NEMO, RIPK3, ZBP1, OPTN and other small molecules and proteins, depending on cellular context. .
Function
Although, RIPK1 has been primarily studied in the context of TNFR signaling, RIPK1 is also activated in response to diverse stimuli.
The kinase domain, while important for necroptotic (programmed necrotic) functions, appears dispensable for pro-survival roles. Kinase activity of RIPK1 is also required for RIPK1-dependent apoptosis in conditions of IAP1/2 depletion, TAK1inhibition/depletion, RIPK3 depletion or MLKL depletion. Also, proteolytic processing of RIPk1, through both caspase-dependent and -independent mechanisms, triggers lethality that is dependent on the generation of one or more specific C-terminal cleavage product(s) of RIPk1 upon stress.
Role in cell survival
It has been shown that cell survival can be regulated through different RIPK1-mediated pathways that ultimately result in the expression of NF-kB, a protein complex known to regulate transcription of DNA and thus, related to survival processes.
Receptor-mediated signalling
The best well-known pathway of NF-kB activation is that mediated by the death receptor TNFR1, which starts as in the necroptosis pathway with the assembly of TRADD, RIPK1, TRAF2 and clAP1 in the lipid rafts of the plasma membrane (complex I is formed). In survival signalling, RIPK1 is then polyubiquitinated, allowing NEMO (Necrosis Factor – kappa – B essential modulator) to bind to the IkB kinase or IKK complex. To activate IKK, TAB2 and TAB3 adaptor proteins recruit TAK1 or MEKK3, which phosphorylate the complex. This results in the phosphorylation of the NF-kB inhibitors by the activated IKK complex, which in turn triggers their polyubiquitination and posterior degradation in the 26S proteasome.
As a result, NF-kB can now migrate to the nucleus where it will control DNA transcription by binding itself to the promoters of specific genes. Some of those genes are thought to have anti-apoptotic properties as well as to promote proteasomal degradation of RIPK1, resulting in a self-regulatory cycle.
While being in complex I, RIPK1 has also been proved to play a role in the activation of MAP (mitogen-activated protein) kinases such as JNK, ERK and p38. In particular, JNK can be found in both cell death and survival pathways, with its role in the cell death process being suppressed by activated NF-kB.
Cell survival signalling can also be mediated by TLR-3 (toll-like receptors) and TLR-4. In here, RIPK1 is recruited to the receptors where it is phosphorylated and polyubiquitinated. This results in the recruit of the IKK complex activating proteins (TAK1, TAB1 and TAB2) so eventually NF-kB can now too migrate to the nucleus. RIPK2 is involved in this TLR-mediated signalling, which suggests that there might be a regulation of cell survival or death (the two possible outcomes) through the mutual interaction between the two RIPK family members.
