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Fig. 1 | Cell Communication and Signaling

Fig. 1

From: Flipping the dogma – phosphatidylserine in non-apoptotic cell death

Fig. 1

Necroptosis molecular pathway. Necroptotic cell death can be triggered by numerous factors, including death receptors, TLRs, and intracellular receptors. The ligation of TNF to its receptor (TNFR1) recruits TNFR type 1-associated via death domain (TRADD) and RIPK1 via their death domain (DD) (pink ellipse). TRADD recruits TNF receptor associated factor 2 (TRAF2) and cellular inhibitors of apoptosis (cIAPs) to collectively form complex I, together with the linear ubiquitin chain assembly complex (LUBAC). In complex I, RIPK1 is ubiquitylated to induce nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB) nuclear translocation and signaling. This signaling results in the expression of inflammatory cytokines and pro-survival proteins, such as c-FLIP. When complex I activity is impaired, or following TNFR1 endocytosis, the assembly of a RIPK1/caspase-8/FADD/c-FLIP cytosolic complex, complex II, can occur. Caspase-8, in complex with c-FLIP, cleaves and inactivates RIPK1 and RIPK3. When caspase-8 activity is blocked, phosphorylation and oligomerization of RIPK3 leads to necroptosis by inducing phosphorylation of MLKL followed by its translocation to the cell membrane. The cellular contents released from necroptotic cells can serve as DAMPs to further induce inflammation. Similarly, when caspase-8 activity is blocked, necroptosis can also be induced by interferons (IFNs) (green ellipse), TLRs (blue ellipse), and DNA-dependent activator of IFN-regulatory factors (DAI) (purple ellipse). IFNs stimulate Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling upon ligation of IFN receptors (IFNRs) resulting in RIPK1 and/or RIPK3 activation. TLRs can recruit RIPK3 via TIR-domain-containing adaptor-inducing interferon- β (TRIF) upon ligation by lipopolysaccharides (LPS) (for TLR4) or dsRNA (for TLR3). DAI directly interacts with RIPK3 via a RHIM-RHIM interaction upon sensing of dsDNA

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