Mixed Lineage Kinase Domain-like Protein Mediates Necrosis Signaling Downstream of RIP3 Kinase
Open accessAbstract
The receptor-interacting serine-threonine kinase 3 (RIP3) is a key signaling molecule in the programmed necrosis (necroptosis) pathway. This pathway plays important roles in a variety of physiological and pathological conditions, including development, tissue damage response, and antiviral immunity. Here, we report the identification of a small molecule called (E)-N-(4-(N-(3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophene-2-yl)acrylamide--hereafter referred to as necrosulfonamide--that specifically blocks necrosis downstream of RIP3 activation. An affinity probe derived from necrosulfonamide and coimmunoprecipitation using anti-RIP3 antibodies both identified the mixed lineage kinase domain-like protein (MLKL) as the interacting target. MLKL was phosphorylated by RIP3 at the threonine 357 and serine 358 residues, and these phosphorylation events were critical for necrosis. Treating cells with necrosulfonamide or knocking down MLKL expression arrested necrosis at a specific step at which RIP3 formed discrete punctae in cells. These findings implicate MLKL as a key mediator of necrosis signaling downstream of the kinase RIP3.
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Essential contribution of MLKL to necroptosis has been confirmed by genetic studies and pharmacological interventions.
“Although the essential contribution of MLKL to necroptosis has been confirmed by genetic studies [435] as well as by pharmacological (i.e., inhibition of MLKL with necrosulfonamide, NSA) interventions [442]”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [442]
Activation of RIPK3 downstream of TNFR1 ligation relies on formation of RIPK1-containing and RIPK3-containing amyloid-like signaling complex known as necrosome, wherein first RIPK1 and then RIPK3 undergo trans-phosphorylation or auto-phosphorylation events required for MLKL recruitment and necroptosis activation.
“In particular, the activation of RIPK3 downstream of TNFR1 ligation relies on the formation of a RIPK1-containing and RIPK3-containing amyloid-like signaling complex commonly known as necrosome [436, 470], wherein first RIPK1 and then RIPK3 undergo a series of trans-phosphorylation or auto-phosphorylation events that are required for MLKL recruitment and necroptosis activation [437, 438, 442, 471]”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [442]
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Zhang, L., Ni, M., Si, J., Cheng, F., Zhang, L., Liang, Y., Liu, M., Li, W., Li, J., Chi, Y., et al. (2026) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2025.101622 · Cited by 1 · see citing works
- Authors
- Sun, L., Wang, H., Wang, Z., He, S., Chen, S., Liao, D., Wang, L., Yan, J., Liu, W., Lei, X., & Wang, X.
- Affiliations
- National Institute of Biological Sciences, Beijing (CN)
- The University of Texas Southwestern Medical Center (US)
- Tianjin University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Corresponding author
- Lei, Xiaoguang
- Wang, Xiaodong
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 148
- Issue
- 1-2
- Pages
- 213-227
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2132161879
- Cited by
- 2,698
- References
- 4
- Citations by year
- 2026: 184 · 2025: 235 · 2024: 246 · 2023: 235 · 2022: 268 · 2021: 267 · 2020: 200 · 2019: 188 · 2018: 189 · 2017: 140 · 2016: 160 · 2015: 130 · 2014: 138 · 2013: 78 · 2012: 36
- FWCI
- 49.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 599 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (5p01ca095471-10)
- National Cancer Institute (P01 CA95471, P30CA142543)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Keywords
- necroptosis, MLKL, necrosulfonamide, MLKL phosphorylation, kinase inhibitors
- MeSH terms
- Acrylamides, Amino Acid Sequence, Animals, Humans, Molecular Sequence Data, Necrosis, Protein Kinases, Sulfonamides, Signal Transduction, Sequence Alignment, Cell Line, Tumor, Mice, Receptor-Interacting Protein Serine-Threonine Kinases, Gene Knockdown Techniques
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