RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL

By K. Lawlor, Nufail R. Khan, A. Mildenhall, M. Gerlic, B. Croker, A. D’Cruz, Cathrine M. Hall, Sukhdeep Kaur Spall, H. Anderton, S. Masters and 10 more. Nature Communications, 2015

623 citations recorded by the source corpus.

RIPK3 and its substrate MLKL are essential for necroptosis, a lytic cell death proposed to cause inflammation via the release of intracellular molecules. Whether and how RIPK3 might drive inflammation in a manner independent of MLKL and cell lysis remains unclear. Here we show that following LPS treatment, or LPS-induced necroptosis, the TLR adaptor protein TRIF and inhibitor of apoptosis proteins (IAPs: X-linked IAP, cellular IAP1 and IAP2) regulate RIPK3 and MLKL ubiquitylation. Hence, when IAPs are absent, LPS triggers RIPK3 to activate caspase-8, promoting apoptosis and NLRP3–caspase-1 activation, independent of RIPK3 kinase activity and MLKL. In contrast, in the absence of both IAPs and caspase-8, RIPK3 kinase activity and MLKL are essential for TLR-induced NLRP3 activation. Consistent with in vitro experiments, interleukin-1 (IL-1)-dependent autoantibody-mediated arthritis is exacerbated in mice lacking IAPs, and is reduced by deletion of RIPK3, but not MLKL. Therefore RIPK3 can promote NLRP3 inflammasome and IL-1β inflammatory responses independent of MLKL and necroptotic cell death. RIPK3 can cause necroptotic cell death via MLKL phosphorylation, and activate NLRP3 inflammasome. Here the authors show that MLKL is dispensable for NLRP3 activation by RIPK3, and highlight how different IAP proteins limit RIPK3 induced apoptosis, necroptosis and IL-1 secretion.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/b0b5b314fa379cb5b41ae680358af7319f50faf8

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. T. Kanneganti
2. R. Malireddi
3. S. Kesavardhana
4. F. Shao
5. Gerald I. Shulman
6. Yan Yu
7. Weitong Gao
8. Yang Zhou

In Molecular Biology

1. T. Kanneganti
2. R. Malireddi
3. S. Kesavardhana
4. F. Shao
5. Gerald I. Shulman
6. Yan Yu
7. Weitong Gao
8. Yang Zhou

Citations in the corpus

• ZBP1 and TAK1: Master Regulators of NLRP3 Inflammasome/Pyroptosis, Apoptosis, and Necroptosis (PAN-optosis) (2019, background): “Moreover, ASC, an important adapter for inflammasome assembly, was also shown to be recruited to the caspase-8–containing cell death complex (Van Opdenbosch et al., 2017; Lee et al., 2018).”
• Necroptosis: Mechanisms and Relevance to Disease (2016, neutral): “…or core components of the necroptotic machinery contribute to various inflammatory disorders, including Crohn disease (68); rheumatoid arthritis (52); multiple sclerosis (178); TNF-driven autoinflammatory disorders, including the so-called systemic inflammatory response syndrome (SIRS) (47,…”
• Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during Yersinia infection (2018, background): “NLRP3 recruits apoptosis-associated speck-like protein (ASC), which then recruits procaspase-1 via homotypic CARD-domain binding (20).”
• Mechanisms and disease consequences of nonalcoholic fatty liver disease (2021, background): “Among other pathways downstream of necroptosis, RIPK3 may activate the NLRP3 inflammasome (Lawlor et al., 2015).”
• Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy (2022, background): “There has been evidence to suggest that necroptosis acts as a tumor suppressor in most cases.(152,153) Two-thirds of samples in a study of more than 60 cancer cell lines showed decreased levels of RIPK3, which indicates that the cancer cells prefer to escape necroptosis and survive.”
• Necroptosis: a regulated inflammatory mode of cell death (2018, background): “Some models explain that RIPK3 also acts as scaffold to recruit complex containing RIPK1, FADD, and caspase-8 [51, 52, 56, 59, 60].”