ReviewCell death

Location, location, location: A compartmentalized view of TNF-induced necroptotic signaling

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Science Signaling  02 Feb 2021:
Vol. 14, Issue 668, eabc6178
DOI: 10.1126/scisignal.abc6178


  • Fig. 1 A variable network of modulators surrounds the core necroptotic signaling axis of TNF-induced necroptosis.

    (A) Summary of the different stimuli and receptors that signal MLKL-mediated death. Necroptotic triggers converge at the core signaling axis (RIPK1-RIPK3-MLKL) and result in phospho-MLKL–mediated membrane lysis. Dashed arrows represent the possible cross-talk between the receptors involved in necroptotic signaling (2326). LPS, lipopolysaccharide; dsRNA, double-stranded RNA; TRAIL, Tumor necrosis factor related apoptosis inducing ligand; IFN, interferon; TLR3, Toll-like receptor 3; DAI, DNA-dependent activator of IFN-regulatory factors. (B) Venn diagram depicting the results of eight genetic screens that identified regulators of TNF-induced necroptosis (27, 28, 4246). The cell lines and necroptotic stimuli used for each screen are listed. The nonoverlapping hits identified in each screen are also enumerated, whereas CYLD (cylindromatosis), SPATA2 (spermatogenesis-associated protein 2), TNFRSF1A, and MALAT1 (metastasis associated lung adenocarcinoma transcript 1) are hits that overlapped between two or more screens. Owing to its central role in TNF-induced necroptosis, the core signaling axis of RIPK1-RIPK3-MLKL has been superimposed over these screen results. siRNA, small interfering RNA; shRNA, short hairpin–mediated RNA. (C) Summary of the domain architecture of human RIPK1, RIPK3, and MLKL. RHIM, RIP homotypic interaction motif; DD, death domain; 4HB, four-helix bundle; Brace, brace helices. Gray arrows indicate critical pronecroptotic phosphorylation events. Dashed black arrows indicate important protein:protein interactions.

  • Fig. 2 The first compartmentalization event in TNF-induced necroptosis.

    Schematic showing that TNFR1 activation leads to the formation of Complex I, which can then promote cell survival and proinflammatory cytokine production. Conversely, particularly when Complex I is internalized and when K11- and K63-linked ubiquitin (Ub) chains are removed from RIPK1, potent cell death signals are transduced that trigger either extrinsic apoptosis or necroptosis. Casp8, Caspase-8; HOIL-2, heme-oxidized IRP2 ubiquitin ligase 1; HOIP, HOIL-1-interacting protein; BIR, baculovirus inhibitor of apoptosis repeat; RING, really interesting new gene.

  • Fig. 3 The second compartmentalization event in TNF-induced necroptosis.

    Internalized Complex I can transform into Complex IIa or Complex IIb when Met1-, K11-, and K63-linked ubiquitin chains are removed from RIPK1 by the deubiquitinase CYLD (61). Whereas Caspase-8 activity within Complex IIa or Complex IIb drives apoptosis, its inhibition leads to the formation of the necrosome. The necrosome preferentially localizes to the perinuclear region of the cytoplasm and recruits multiple proteins, including MLKL. The activation of MLKL within the necrosome then allows it to mediate downstream necroptotic events.

  • Fig. 4 The third compartmentalization event in TNF-induced necroptosis.

    Necroptosis can be instigated in scenarios in which cIAP1/2 and Caspase-8 abundance or activity are compromised. Downstream of pathway initiation, MLKL departs from the necrosome toward its primary destination, the plasma membrane. Here, MLKL accumulates into supramolecular structures known as hotspots and eventually triggers necroptosis by lysing the membrane. Plasma membrane rupture promotes the release of DAMPs including high mobility group box protein 1 (HMGB1), adenosine triphosphate (ATP), and lactate dehydrogenase (LDH), which, in turn, are paracrine signals that induce ongoing inflammation and immune reactivity (188). In many, but not all cell types, MLKL is actively trafficked from the necrosome to the plasma membrane through Golgi-, microtubule-, and actin-dependent mechanisms. Necroptosis can also be prevented by the endocytic or exocytic removal of activated MLKL from the plasma membrane. The former is mediated by Flotillin and the latter is mediated by Rab27a or Rab27b, ALIX, syntenin-1, and other components of the ESCRT-III complex. Whether MLKL resides within the lumen or associates with the external face of endosomes and exosomes is currently unclear. BIR, baculovirus inhibitor of apoptosis repeat.


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