MLKL and FADD Are Critical for Suppressing Progressive Lymphoproliferative Disease and Activating the NLRP3 Inflammasome
Open accessAbstract
MLKL, a key component downstream of RIPK3, is suggested to be a terminal executor of necroptosis. Genetic studies have revealed that Ripk3 ablation rescues embryonic lethality in Fadd- or Caspase-8-deficient mice. Given that RIPK3 has also been implicated in non-necroptotic pathways including apoptosis and inflammatory signaling, it remains unclear whether the lethality in Fadd(-/-) mice is indeed caused by necropotosis. Here, we show that genetic deletion of Mlkl rescues the developmental defect in Fadd-deficient mice and that Fadd(-/-)Mlkl(-/-) mice are viable and fertile. Mlkl(-/-)Fadd(-/-) mice display significantly accelerated lymphoproliferative disease characterized by lymphadenopathy and splenomegaly when compared to Ripk3(-/-)Fadd(-/-) mice. Mlkl(-/-)Fadd(-/-) bone-marrow-derived macrophages and dendritic cells have impaired NLRP3 inflammasome activation associated with defects in ASC speck formation and NF-κB-dependent NLRP3 transcription. Our findings reveal that MLKL and FADD play critical roles in preventing lymphoproliferative disease and activating the NLRP3 inflammasome.
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Embryonic lethality imposed on mice by loss of Casp8 or Fadd can be rescued by concurrent ablation of Ripk3 or Mlkl, even though double knockout animals generally display lymphoproliferative and/or systemic autoimmune disorders as adults.
“Thus, the embryonic lethality imposed on mice by the loss of Casp8 or Fadd can be rescued by concurrent ablation of Ripk3 or Mlkl, even though these double knockout animals generally display lymphoproliferative and/or systemic autoimmune disorders as adults [432, 466, 484, 485].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [432]
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- Authors
- Zhang, X., Fan, C., Zhang, H., Zhao, Q., Liu, Y., Xu, C., Xie, Q., Wu, X., Yu, X., Zhang, J., & Zhang, H.
- Affiliations
- Chinese Academy of Sciences (CN)
- Second Military Medical University (CN)
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2016-09
- Volume
- 16
- Issue
- 12
- Pages
- 3247-3259
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC7191534
- OpenAlex
- W2489489141
- Cited by
- 93
- References
- 52
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 4 · 2023: 9 · 2022: 10 · 2021: 9 · 2020: 11 · 2019: 10 · 2018: 11 · 2017: 14 · 2016: 2
- FWCI
- 6.41
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- The Medicine Forum (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Recruitment Program of Global Experts
- Thousand Young Talents Program of China
- National Cancer Institute (P30CA056036)
- National Institute of Allergy and Infectious Diseases (R01AI119069, R21AI105794)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- MLKL, FADD, RIPK3, necroptosis, lymphoproliferative disorders, NLRP3 inflammasome, ASC speck formation, NF-κB, caspase-8, macrophages, dendritic cells, lymphadenopathy, splenomegaly
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Lymphoproliferative Disorders, Mice, Inbred C57BL, Protein Kinases, Mice, Knockout, Mice, Fas-Associated Death Domain Protein, Inflammasomes
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