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. 2022 Jul 22;13(7):637. doi: 10.1038/s41419-022-05066-3

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© The Author(s) 2022

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 2 — Various stimuli, including the TLRs, IFN, death ligands, and pathogenic infections (Viruses, Bacteria, and Parasites), can induce cell death in necroptosis. TNF engages with its receptor and induces cell apoptosis by inhibiting cIAP or deubiquitination of RIP1 by cylindromatosis (CYLD). Instead, inhibition of FADD or caspase-8 can sensitize the cells to undergo necroptosis. Microbial infections can also initiate necroptosis via activation of the receptor-interacting protein kinase 1 (RIP1) and RIP3 complex. Further phosphorylation of MLKL by RIP3 can induce the oligomerization and translocation of MLKL to the membrane, eventually causing cell death. Besides the RIP1-RIP3-MLKL dependent-necroptosis, some RHIM-containing factors like TRIF and IFN-regulatory factors (DAI, also known as ZBP1) mediate the noncanonical necroptosis without the involvement of RIP1. TLRs Toll-like receptors, IFN interferon, FADD Fas-associated protein with death-domain, MLKL mixed lineage kinase domain-like, RHIM RIP homology interaction motifs (RHIM), ZBP1 Z-DNA-binding protein 1.