Fig. 2: Post-translational modification of RIPK1. | Cell Death Discovery

Fig. 2: Post-translational modification of RIPK1.

From: Regulated cell death in hypoxic-ischaemic encephalopathy: recent development and mechanistic overview

Fig. 2

Binding of the tumour necrosis factor superfamily (TNFSF) to the tumour necrosis factor receptor superfamily (TNFRSF) leads to TRADD (TNFR1-associated DD protein)-dependent recruitment of receptor-interacting protein kinase (RIPK1) through homotypic interaction. The E3 ubiquitin ligase cellular inhibitor of apoptosis 1 or 2 (cIAP1/2) is subsequently recruited by TNFR-associated factor 2 (TRAF2) to promote K63 ubiquitination (ub, grey circles) of RIPK1 to form the K63 polyubiquitin linkage. The K63 linkage facilitates the recruitment and activation of transforming growth factor β-activated kinase 1 (TAK1) via TAK-associated binding protein 2 and 3 (TAB2/3) to induce the pro-survival MAPK signalling pathway. The presence of K63 linkage further promotes the recruitment of linear ubiquitination assembly complex (LUBAC) to lead to M1 (linear) polyubiquitination of RIPK1 (ub, grey circlesO. The M1 ubiquitin linkage is recognised by NFκB essential modulator (NEMO) and inhibitor of κB kinases (IκK) to stimulate the NFκB signalling pathway and upregulate the transcription of pro-inflammatory cytokines; transcription of anti-apoptotic proteins such as cIAP and c-FLIP (cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory peptide) is also activated by NFκB. Endogenous deubiquitinases such as CYLD and A20 can also be recruited to dissemble the M1 and K63 polyubiquitin linkages. Moreover, TAK1 and TANK-binding kinase 1 (TBK1) could mediate the inhibitory phosphorylation of RIPK1. The aggregation and stabilisation of RIPK1 with the collection of post-translational editing enzymes is termed as complex I. In addition to poly-ubiquitination, proline residues on RIPK1 are hydroxylated (OH, red circles) by the prolyl hydroxylase enzyme Egl nine homologues (EGLNs) and the hydroxylated RIPK1 interacts with von Hippel Lindau protein (pVHL) to prevent downstream RIPK1 signalling. Hypoxia prevents EGLNs-mediated RIPK1 prolyl hydroxylation to avoid the negative regulation by pVHL. Taken together, when RIPK1 becomes deubiquitinated (e.g. cIAP inhibition by SMAC/DIABLO or SMAC synthetics, NEMO knockout or TAK1 knockout, upregulation of CYLD and A20) and dehydroxylated during hypoxia, RIPK1 is released from an “inactive” state and resumes its kinase activity to activate apoptosis or necroptosis pathways. cIAP1/2 cellular inhibitor of apoptosis 1 or 2, c-FLIP cellular FLICE inhibitory peptide, CYLD cylindromatosis tumour suppressor protein, DIABLO direct inhibitor of apoptosis-binding protein with low pI, EGLN Egl nine homologues, FLICE FADD-like IL-1β-converting enzyme, IκK inhibitor of κB kinases, LUBAC linear ubiquitination assembly complex, MAPK mitogen activated protein kinase, NEMO NFκB essential modulator, NFκB nuclear factor kappa B, OH hydroxylation, RIPK1 receptor interacting protein kinase 1, SMAC second mitochondria-derived activator of caspase, TAB2/3 TAK-associated binding protein 2 and 3, TAK1 transforming growth factor β-activated kinase 1, TBK1 TANK-binding kinase 1, TNFSF tumour necrosis factor superfamily, TNFRSF tumour necrosis factor receptor superfamily, TRADD TNFR1-associated DD protein, TRAF2 TNFR-associated factor 2, ub ubiquitination, pVHL von Hippel Lindau protein. Created with BioRender.com.

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