Fig. 2: Direct interacting partners of main necroptotic signaling molecules.
From: Current translational potential and underlying molecular mechanisms of necroptosis
Sp1 transcription factor increases RIPK3 expression. INFγ-mediated up-regulation of RIPK3 and MKLK level depend on JAK1 kinase, and STAT1 and IRF transcription factors. BRD4 cooperating with IRF1 also increase MLKL transcription. Hypermethylation of the RIPK3 promoter by UHRF1 results in silenced RIPK3 expression. The stability of all RIPK1, RIPK3 and MLKL proteins are increased by HSP90 and CDC37 co-chaperone complex and by FKBP12. The level of both RIPK1 and RIPK3 are down-regulated by caspase-8-mediated cleavage. Cathepsins are also capable of processing RIPK1. A20, CHIP, Optn, PELI1 and Triad3a ubiquitin-ligases mediate K48-linked polyubiquitylation and the subsequent proteasome dependent degradation of: RIPK1, RIPK3 and/or MLKL Upon necroptosis human RIPK1 is autophosphorylated at ser14, ser15, ser161, ser166 and RIPK3 at ser199 and ser227 and ser277. The transient phosphorylation of RIPK1 at ser321 is phosphorylated transiently by TAK1 leads to RIPK1-independent apoptosis and the sustained phosphorylation of RIPK1 by TAK1 at ser321, ser332, ser334 and ser336 induces RIPK1 kinase activation106. IKKα/IKKβ also phosphorylate RIPK1 at ser25 and thereby block RIPK1 activity108,214,215. Mitogen-activated protein kinase-activated protein kinase 2 (MK2) mediates phosphorylation of RIPK1 at ser321 and ser336 and restrains integration of RIPK1 into the cytosolic death complex107,216,217. The phosphorylation at ser89 by a currently unknown kinase inhibits the RIPK1 kinase activity218. Ubiquitylation of RIPK1 at Lys115 by PELI219 or Lys377 by cIAP1, cIAP2 and Parkin220 promotes necroptosis. LUBAC complex and the deubiquitinase CYLD regulates M1 ubiquitination of RIPK1221. Lys363 ubiquitylation of RIPK3 leads to its proteasomal degradation. RIPK3 is responsible for the phosphorylation of MLKL at thr357 and ser358. TAM (Tyro3, Axl, and Mer) family of receptor tyrosine kinases phosphorylate MLKL on Tyr376 to facilitate MLKL oligomerization145. MLKL is also phosphorylated on Ser441 by a still unidentified kinase222. Caspase-8 mediates the cleavage and inactivation of RIPK1 at asp324 and RIPK3 at asp328. O-GlcNAcylation of the RIPK3 at thr467 by OGT prevents necroptosis223. Red names indicate interaction partners of RIPK1, RIPK3, MLKL which activate necroptosis, blue marks necroptosis inhibitors
