Table 1.
Key proteins involved in necroptosis
| Protein | Role in necroptosis | Initial amount | UniProt ID | Refs. |
|---|---|---|---|---|
| A20 | Ubiquitin-editing enzyme responsible for deubiquitinating RIP1 in complex I | 0.225 μM (8868 molecules) | F8K9X7 | (13,21) |
| Caspase-8 | Heterodimerizes with cFLIPL (long isoform), leading to cleavage and inactivation of RIP1 and RIP3 in complex II | 0.096 μM (3799 molecules) | Q14790 | (42,107) |
| cFLIPL | Heterodimerizes with caspase-8, leading to cleavage and inactivation of RIP1 and RIP3 in complex II | 0.081 μM (3193 molecules) | O15519 | (43,108) |
| cIAP1/2 | Catalyzes, via its RING domains, the activating K63-linked polyubiquitination of RIP1 | 0.225 μM (8868 molecules) | Q13075, Q13490 | (25,81) |
| CYLD | Deubiquitinates RIP1 in either complex I or within the RIP1-RIP3 necrosome | 0.225 μM (8868 molecules) | Q9NQC7 | (11,17) |
| FADD | TNFR1-interacting scaffold protein in complex II | 0.079 μM (3109 molecules) | Q13158 | (18,109,110) |
| LUBAC | TNFR1-interacting protein complex (composed of HOIL-1 and HOIP) recruited by cIAP1/2 in complex I that promotes RIP1 ubiquitination | 0.180 μM (7095 molecules) | Q9BYM8, Q96EP0 | (25,82) |
| MLKL | Recruited to the necrosome by RIP1, where it is phosphorylated, leading to cell death by membrane rupture | 0.141 μM (5544 molecules) | Q9BYM8, Q96EP0 | (48,111,112) |
| RIP1 | A multifunctional adaptor protein in the necrosome that recruits and activates RIP3 and MLKL | 0.500 μM (19,707 molecules) | Q8NB16 | (25,113,114) |
| RIP3 | Recruited to the necrosome by binding to and cross-phosphorylating RIP1 | 0.270 μM (10,654 molecules) | Q9Y572 | (111,115,116) |
| TNF | Pleiotropic proinflammatory cytokine that activates necroptosis in the absence of caspase activity | 0.1–100 ng/mL (2–2413 molecules) | Q13546 | (117) |
| TNFR1 | TNF receptor superfamily member death receptor that recruits RIP1 to complex 1 | 0.125 μM (4927 molecules) | Q9Y572 | (33,118) |
| TRADD | TNFR1-interacting protein in complexes I and II that serves as a docking adaptor for the binding of RIP1 to TRAF2 | 0.119 μM (4696 molecules) | P01375 | (35,118) |
| TRAF2 | TNFR1-interacting protein that recruits cIAP1/2 to complex I, promoting K63-linked RIP1 ubiquitination | 0.299 μM (11,776 molecules) | P19438 | (109,119) |
Initial amounts are based on either mass spectrometry measurements (this work) or estimates from the literature (see materials and methods). All UniProt IDs (www.uniprot.org) are for human proteins.