Table 1 Potential common mechanisms-of-action identified by new necroptosis regulators
From: CRISPR whole-genome screening identifies new necroptosis regulators and RIPK1 alternative splicing
Gene class | Gene (alias) | Gene functionsa | Protein class or domainsa |
|---|---|---|---|
Inflammatory and apoptotic signaling | N4bp1 | Substrate and inhibitor of pro-apoptotic and anti-inflammatory ITCH, which destabilizes RIPK1 (through A20) and TAK1 (through CYLD) | KH (RNA binding), UBA (ubiquitin interaction), and NYN (RNAse) domains |
|  | Traf1 | Dimerizes with TRAF2 to mediate TNFR1 activation of JNK, NF-κB, and anti-apoptotic signals | Adaptor protein |
|  | Nfkbia (IκBα) | Blocks nuclear import of NF-κB/Rel, and Bax recruitment to VDAC1 | Ankyrin repeats |
| Â | Usp9x | Stabilizes ITCH, MCL1, and XIAP | Deubiquitinase |
|  | Ube2k (Hip2) | Promotes TNFα-mediated NF-κB activation; destabilizes Smac/DIABLO, p53, and Rb | Ubiquitin-conjugating enzyme |
WNK-OSR1/SPAK signaling | Oxsr1 (Osr1) | Activates Na(+)-K(+)-2Cl(-) cotransporters; inhibits K(+)-Cl(-) cotransporters; osmoregulation; ischemic neuronal cell death | Ser/Thr protien kinase |
| Â | Wnk1 | Activates OXSR1 and paralog STK39/SPAK; cell volume recovery during osmotic stress; inhibits autophagy | Ser/Thr protein kinase |
Lysosome-endosome-Golgi-ER trafficking and function | C030046E11Rik (Ric1) | Retrograde transport from endosomes to Golgi; Ric1-Rgp1 complex is GEF for late Golgi Rab6A GTPase | WD40 repeat |
| Â | Rgp1 | Retrograde transport from endosomes to Golgi; Ric1-Rgp1 complex is GEF for late Golgi Rab6A GTPase | Â |
| Â | Cog1 (Ldlb) | Intra-Golgi vesicle, endosome-Golgi, and Golgi-ER retrograde transport to maintain Golgi structure and function | Â |
| Â | Cog3 (Sec34) | Intra-Golgi vesicle, endosome-Golgi, and Golgi-ER retrograde transport to maintain Golgi structure and function | Â |
| Â | Cog4 (Cod1) | Intra-Golgi vesicle, endosome-Golgi, and Golgi-ER retrograde transport to maintain Golgi structure and function | Â |
| Â | Cog6 (Cod2, Cdg2l) | Intra-Golgi vesicle, endosome-Golgi, and Golgi-ER retrograde transport to maintain Golgi structure and function | Â |
| Â | Arfrp1 (Arp1, rl18) | Retrograde transport from endosomes to Golgi; Golgi-to-plasma membrane transport | Plasma membrane-associated GTPase |
| Â | Vps29 | Retrograde transport from endosomes to Golgi or plasma membrane; retromer complex component | Metallophosphatase superfamily (inactive) |
| Â | Tmed9 (Gmp25, p24alpha2) | Cargo receptor for Golgi-ER retrograde transport (COPI complex component); promotes ER exit of proteins | Â |
| Â | Sec23ip (p125A) | ER-Golgi anterograde transport (COPII complex component) | Phospholipase A1 family; SAM domain |
| Â | Atp6ap2 (prorenin receptor) | Stabilizes V-ATPase; acidification of endodomes and lysosomes; endolysosomal protein sorting and degradation; adaptor between V-ATPase and Wnt receptor complex | Â |
| Â | Atp6ap1 (Ac45) | Promotes V-ATPases activity; acidification of endodomes and lysosomes; calcium-dependent membrane fusion | Â |
Nonsense-mediated mRNA decay (NMD) | Smg7 | NMD; stabilizes p53 (promotes ATM phosphorylation of MDM2) | Est1 DNA/RNA binding domain |
| Â | Smg8 | NMD | Â |
| Â | Upf2 | NMD; mRNA nuclear export | Â |
| Â | Xrn1 | Decapped mRNA degradation; NMD | Exonuclease |
| Â | Ddx6 (Rck) | DCP1 mRNA decapping complex activator; mRNA degradation, translation, and/or translational repression | DEAD-box helicase |
mRNA splicing | Ptbp1 | Alternative splicing factor; binds mRNA polypyrimidine tracts | RRM (RNA binding) domains |
| Â | Pcbp1 | mRNA processing; binds mRNA poly(rC); iron chaperone for metalloproteins | KH (RNA binding) domains |
| Â | Mettl3 | N6-methyladenosine [m(6)A]:RNA methyltransferase; regulates splicing and mRNA export, translation, and decay | Â |
| Â | Ythdc1 (Yt521) | mRNA methylation [m(6)A] reader protein; alternative splicing factor | YTH [m(6)A-binding] domain |
