ArticleCell death & disease2022
Human RIPK3 C-lobe phosphorylation is essential for necroptotic signaling.
Article in Cell death & disease, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 27 citations in OpenAlex.
- The kinase domain of RIPK3 tunes its scaffolding functions.Cell death and differentiation · 2026Article
- PANoptosis as a drug discovery framework: integrating cell death architecture with clinical translation.Genes and immunity · 2026Review
- Autoinhibitory control of MLKL governs pseudokinase domain phosphorylation and oligomerization during necroptosis.Cell reports · 2026Article
- Immune molecular mechanisms of PANoptosis in sepsis-induced acute kidney injury.Inflammation and regeneration · 2026Review
- Focus on necroptosis: its role in the pathogenesis and therapeutic potential of osteoarthritis.Frontiers in immunology · 2026Review
- GADD45β inhibits RIPK3-mediated NF-κB activation by interfering with NEMO-RIPK1-RIPK3 interactions.Cell death discovery · 2025Article
- Necroptotic cell death consequences and disease relevance.Nature immunology · 2025Review
- Mixed Lineage Kinase Domain-Like Protein (MLKL): From Mechanisms to Therapeutic Opportunities.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- The Role of Post-Translational Modifications in Necroptosis.Biomolecules · 2025Review
- Inhibitors identify an auxiliary role for mTOR signalling in necroptosis execution downstream of MLKL activation.The Biochemical journal · 2024Article
- Immunogenic cell death in cancer: targeting necroptosis to induce antitumour immunity.Nature reviews. Cancer · 2024Review
- RIP3 in Necroptosis: Underlying Contributions to Traumatic Brain Injury.Neurochemical research · 2024Review
- Phosphorylation-dependent pseudokinase domain dimerization drives full-length MLKL oligomerization.Nature communications · 2023Article
- Repurposing of Ibrutinib and Quizartinib as potent inhibitors of necroptosis.Communications biology · 2023Article
- The VEGFR/PDGFR tyrosine kinase inhibitor, ABT-869, blocks necroptosis by targeting RIPK1 kinase.The Biochemical journal · 2023Article
- Role of necroptosis in kidney health and disease.Nature reviews. Nephrology · 2023Review
- Breaking bad: necroptosis in the pathogenesis of gastrointestinal diseases.Frontiers in immunology · 2023Review
- RIPK1 and RIPK3 inhibitors: potential weapons against inflammation to treat diabetic complications.Frontiers in immunology · 2023Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Necroptosis is a caspase-independent, pro-inflammatory mode of programmed cell death which relies on the activation of the terminal effector, MLKL, by the upstream protein kinase RIPK3. To mediate necroptosis, RIPK3 must stably interact with, and phosphorylate the pseudokinase domain of MLKL, although the precise molecular cues that provoke RIPK3 necroptotic signaling are incompletely understood. The recent finding that RIPK3 S227 phosphorylation and the occurrence of a stable RIPK3:MLKL complex in human cells prior to exposure to a necroptosis stimulus raises the possibility that additional, as-yet-unidentified phosphorylation events activate RIPK3 upon initiation of necroptosis signaling. Here, we sought to identify phosphorylation sites of RIPK3 and dissect their regulatory functions. Phosphoproteomics identified 21 phosphorylation sites in HT29 cells overexpressing human RIPK3. By comparing cells expressing wild-type and kinase-inactive D142N RIPK3, autophosphorylation sites and substrates of other cellular kinases were distinguished. Of these 21 phosphosites, mutational analyses identified only pT224 and pS227 as crucial, synergistic sites for stable interaction with MLKL to promote necroptosis, while the recently reported activation loop phosphorylation at S164/T165 negatively regulate the kinase activity of RIPK3. Despite being able to phosphorylate MLKL to a similar or higher extent than wild-type RIPK3, mutation of T224, S227, or the RHIM in RIPK3 attenuated necroptosis. This finding highlights the stable recruitment of human MLKL by RIPK3 to the necrosome as an essential checkpoint in necroptosis signaling, which is independent from and precedes the phosphorylation of MLKL.
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