RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation
Open accessAbstract
Receptor-interacting protein kinase 1 (RIPK1) regulates cell death and inflammation through kinase-dependent and -independent functions. RIPK1 kinase activity induces caspase-8-dependent apoptosis and RIPK3 and mixed lineage kinase like (MLKL)-dependent necroptosis. In addition, RIPK1 inhibits apoptosis and necroptosis through kinase-independent functions, which are important for late embryonic development and the prevention of inflammation in epithelial barriers. The mechanism by which RIPK1 counteracts RIPK3-MLKL-mediated necroptosis has remained unknown. Here we show that RIPK1 prevents skin inflammation by inhibiting activation of RIPK3-MLKL-dependent necroptosis mediated by Z-DNA binding protein 1 (ZBP1, also known as DAI or DLM1). ZBP1 deficiency inhibited keratinocyte necroptosis and skin inflammation in mice with epidermis-specific RIPK1 knockout. Moreover, mutation of the conserved RIP homotypic interaction motif (RHIM) of endogenous mouse RIPK1 (RIPK1 mRHIM) caused perinatal lethality that was prevented by RIPK3, MLKL or ZBP1 deficiency. Furthermore, mice expressing only RIPK1 mRHIM in keratinocytes developed skin inflammation that was abrogated by MLKL or ZBP1 deficiency. Mechanistically, ZBP1 interacted strongly with phosphorylated RIPK3 in cells expressing RIPK1 mRHIM, suggesting that the RIPK1 RHIM prevents ZBP1 from binding and activating RIPK3. Collectively, these results show that RIPK1 prevents perinatal death as well as skin inflammation in adult mice by inhibiting ZBP1-induced necroptosis. Furthermore, these findings identify ZBP1 as a critical mediator of inflammation beyond its previously known role in antiviral defence and suggest that ZBP1 might be implicated in the pathogenesis of necroptosis-associated inflammatory diseases.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
RIPK3 can be activated following RHIM-dependent interaction with ZBP1, which operates as sensor for cytosolic DNA-promoting type I IFN synthesis and NF-κB activation.
“or (2) ZBP1, which operates as a sensor for cytosolic DNA-promoting type I interferon (IFN) synthesis and NF-κB activation [439–441].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [440]
Absence of Ripk1 from keratinocytes promotes spontaneous necroptosis and consequent cutaneous inflammation, which can be prevented by co-deletion of Ripk3, Mlkl, or Zbp1 but not Fadd.
“Likewise, the absence of Ripk1 from keratinocytes promotes spontaneous necroptosis and consequent cutaneous inflammation, which can be prevented by the co-deletion of Ripk3, Mlkl, or Zbp1 but not Fadd [440, 502].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [440]
ZBP1 acts at initial steps of necroptosis by mediating sequential activation of RIPK3 and MLKL.
“ZBP1 acts at the initial steps of necroptosis by mediating the sequential activation of RIPK3 and MLKL.”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [440]
Mice expressing variant of RIPK1 mutated in RHIM domain die perinatally, a phenotype that can be rescued by concurrent Ripk3, Mlkl, or Zbp1 (but not Ticam1) deletion, as well as by knock-in of catalytically inactive RIPK3 or RIPK3 mutated in RHIM domain.
“Moreover, mice expressing a variant of RIPK1 mutated in the RHIM domain die perinatally, a phenotype that can be rescued by concurrent Ripk3, Mlkl, or Zbp1 (but not Ticam1) deletion, as well as by the knock-in of catalytically inactive RIPK3 or RIPK3 mutated in the RHIM domain [440, 441].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [440]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury
Degterev, A., Huang, Z., Boyce, M., Li, Y., Jagtap, P., Mizushima, N., Cuny, G. D., Mitchison, T. J., Moskowitz, M. A., & Yuan, J. (2005) · Nature Chemical Biology · doi:10.1038/nchembio711 · Cited by 3,068 · see citing works
Cho, Y., Challa, S., Moquin, D., Genga, R., Ray, T. D., Guildford, M., & Chan, F. K.-M. (2009) · Cell · doi:10.1016/j.cell.2009.05.037 · Cited by 2,435 · see citing works
Neutral red uptake assay for the estimation of cell viability/cytotoxicity
Repetto, G., del Peso, A., & Zurita, J. L. (2008) · Nature Protocols · doi:10.1038/nprot.2008.75 · Cited by 2,217 · see citing works
Receptor Interacting Protein Kinase-3 Determines Cellular Necrotic Response to TNF-α
He, S., Wang, L., Miao, L., Wang, T., Du, F., Zhao, L., & Wang, X. (2009) · Cell · doi:10.1016/j.cell.2009.05.021 · Cited by 2,214 · see citing works
Necroptosis and its role in inflammation
Pasparakis, M., & Vandenabeele, P. (2015) · Nature · doi:10.1038/nature14191 · Cited by 2,148 · see citing works
Self-citationDAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response
Takaoka, A., Wang, Z., Choi, M. K., Yanai, H., Negishi, H., Ban, T., Lu, Y., Miyagishi, M., Kodama, T., Honda, K., et al. (2007) · Nature · doi:10.1038/nature06013 · Cited by 1,704 · see citing works
TNF-α Induces Two Distinct Caspase-8 Activation Pathways
Wang, L., Du, F., & Wang, X. (2008) · Cell · doi:10.1016/j.cell.2008.03.036 · Cited by 1,352 · see citing works
The Death Domain Kinase RIP Mediates the TNF-Induced NF-κB Signal
Kelliher, M. A., Grimm, S., Ishida, Y., Kuo, F., Stanger, B. Z., & Leder, P. (1998) · Immunity · doi:10.1016/s1074-7613(00)80535-x · Cited by 1,102 · see citing works
Kuriakose, T., Man, S. M., Subbarao Malireddi, R. K., Karki, R., Kesavardhana, S., Place, D. E., Neale, G., Vogel, P., & Kanneganti, T.-D. (2016) · Science Immunology · doi:10.1126/sciimmunol.aag2045 · Cited by 818 · see citing works
Upton, J. W., Kaiser, W. J., & Mocarski, E. S. (2012) · Cell Host & Microbe · doi:10.1016/j.chom.2012.01.016 · Cited by 758 · see citing works
TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines
Ishii, K. J., Kawagoe, T., Koyama, S., Matsui, K., Kumar, H., Kawai, T., Uematsu, S., Takeuchi, O., Takeshita, F., Coban, C., et al. (2008) · Nature · doi:10.1038/nature06537 · Cited by 628 · see citing works
RIPK1 Regulates RIPK3-MLKL-Driven Systemic Inflammation and Emergency Hematopoiesis
Rickard, J. A., O’Donnell, J. A., Evans, J. M., Lalaoui, N., Poh, A. R., Rogers, T., Vince, J. E., Lawlor, K. E., Ninnis, R. L., Anderton, H., et al. (2014) · Cell · doi:10.1016/j.cell.2014.04.019 · Cited by 589 · see citing works
RIPK1 Blocks Early Postnatal Lethality Mediated by Caspase-8 and RIPK3
Dillon, C. P., Weinlich, R., Rodriguez, D. A., Cripps, J. G., Quarato, G., Gurung, P., Verbist, K. C., Brewer, T. L., Llambi, F., Gong, Y.-N., et al. (2014) · Cell · doi:10.1016/j.cell.2014.04.018 · Cited by 562 · see citing works
Newton, K., Sun, X., & Dixit, V. M. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.4.1464-1469.2004 · Cited by 544 · see citing works
RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis
Dannappel, M., Vlantis, K., Kumari, S., Polykratis, A., Kim, C., Wachsmuth, L., Eftychi, C., Lin, J., Corona, T., Hermance, N., et al. (2014) · Nature · doi:10.1038/nature13608 · Cited by 534 · see citing works
Self-citationThe diverse role of RIP kinases in necroptosis and inflammation
Silke, J., Rickard, J. A., & Gerlic, M. (2015) · Nature Immunology · doi:10.1038/ni.3206 · Cited by 522 · see citing works
Berger, S. B., Kasparcova, V., Hoffman, S., Swift, B., Dare, L., Schaeffer, M., Capriotti, C., Cook, M., Finger, J., Hughes-Earle, A., et al. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1400499 · Cited by 374 · see citing works
RIPK1 and RIPK3: critical regulators of inflammation and cell death
Newton, K. (2015) · Trends in Cell Biology · doi:10.1016/j.tcb.2015.01.001 · Cited by 367 · see citing works
DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic interaction motifs to activate NF‐κB
Rebsamen, M., Heinz, L. X., Meylan, E., Michallet, M., Schroder, K., Hofmann, K., Vázquez, J., Benedict, C. A., & Tschopp, J. (2009) · EMBO Reports · doi:10.1038/embor.2009.109 · Cited by 365 · see citing works
Programmed Necrosis in the Cross Talk of Cell Death and Inflammation
Chan, F. K.-M., Luz, N. F., & Moriwaki, K. (2014) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032414-112248 · Cited by 350 · see citing works
Polykratis, A., Hermance, N. M., Zelic, M., Roderick, J. E., KIM, C. S., Van, T.-M., Lee, T. H., Chan, F. K.-M., Pasparakis, M., & Kelliher, M. A. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1400590 · Cited by 328 · see citing works
Self-citationRIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis
Takahashi, N., Vereecke, L., Bertrand, M. J. M., Duprez, L., Berger, S. B., Divert, T., Gonçalves, A., Sze, M., Gilbert, B., Kourula, S., et al. (2014) · Nature · doi:10.1038/nature13706 · Cited by 318 · see citing works
Structure of the DLM-1–Z-DNA complex reveals a conserved family of Z-DNA-binding proteins
Schwartz, T., Behlke, J., Lowenhaupt, K., Heinemann, U., & Rich, A. (2018) · Nature Structural Biology · doi:10.1038/nsb0901-761 · Cited by 297 · see citing works
Bonnet, M. C., Preukschat, D., Welz, P.-S., van Loo, G., Ermolaeva, M. A., Bloch, W., Haase, I., & Pasparakis, M. (2011) · Immunity · doi:10.1016/j.immuni.2011.08.014 · Cited by 295 · see citing works
Self-citationRIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition
Kaiser, W. J., Daley-Bauer, L. P., Thapa, R. J., Mandal, P., Berger, S. B., Huang, C., Sundararajan, A., Guo, H., Roback, L., Speck, S. H., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1401857111 · Cited by 291 · see citing works
Kaiser, W. J., Upton, J. W., & Mocarski, E. S. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.9.6427 · Cited by 277 · see citing works
Control of Life-or-Death Decisions by RIP1 Kinase
Christofferson, D. E., Li, Y., & Yuan, J. (2013) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021113-170259 · Cited by 200 · see citing works
Keratin 14 Cre transgenic mice authenticate keratin 14 as an oocyte‐expressed protein
Hafner, M., Wenk, J., Nenci, A., Pasparakis, M., Scharffetter‐Kochanek, K., Smyth, N. R., Peters, T., Keß, D., Holtkötter, O., Shephard, P., et al. (2004) · genesis · doi:10.1002/gene.20016 · Cited by 167 · see citing works
Self-citationFu, Y., Comella, N., Tognazzi, K., Brown, L. F., Dvorak, H. F., & Kocher, O. N. (1999) · Gene · doi:10.1016/s0378-1119(99)00419-9 · Cited by 162 · see citing works
RIP1-driven autoinflammation targets IL-1α independently of inflammasomes and RIP3
Lukens, J. R., Vogel, P., Johnson, G. R., Kelliher, M. A., Iwakura, Y., Lamkanfi, M., & Kanneganti, T. (2013) · Nature · doi:10.1038/nature12174 · Cited by 157 · see citing works
The Two Faces of Receptor Interacting Protein Kinase-1
Weinlich, R., & Green, D. R. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.11.001 · Cited by 127 · see citing works
RIP3-mediated necrotic cell death accelerates systematic inflammation and mortality
Meng, L., Jin, W., & Wang, X. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1514730112 · Cited by 109 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
Self-citationPyroptosis versus necroptosis: similarities, differences, and crosstalk
Frank, D., & Vince, J. E. (2019) · Cell Death & Differentiation · doi:10.1038/s41418-018-0212-6 · Cited by 1,062 · see citing works
Initiation and execution mechanisms of necroptosis: an overview
Grootjans, S., Vanden Berghe, T., & Vandenabeele, P. (2017) · Cell Death & Differentiation · doi:10.1038/cdd.2017.65 · Cited by 566 · see citing works
Gasdermin E–mediated target cell pyroptosis by CAR T cells triggers cytokine release syndrome
Liu, Y., Fang, Y., Chen, X., Wang, Z., Liang, X., Zhang, T., Liu, M., Zhou, N., Lv, J., Tang, K., et al. (2020) · Science Immunology · doi:10.1126/sciimmunol.aax7969 · Cited by 566 · see citing works
Samir, P., Malireddi, R. K. S., & Kanneganti, T.-D. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.00238 · Cited by 557 · see citing works
Wang, Y., & Kanneganti, T.-D. (2021) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2021.07.038 · Cited by 545 · see citing works
Cytosolic DNA Sensing in Organismal Tumor Control
Vanpouille-Box, C., Demaria, S., Formenti, S. C., & Galluzzi, L. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.05.013 · Cited by 250 · see citing works
Sensing of viral and endogenous RNA by ZBP1/DAI induces necroptosis
Maelfait, J., Liverpool, L., Bridgeman, A., Ragan, K. B., Upton, J. W., & Rehwinkel, J. (2017) · The EMBO Journal · doi:10.15252/embj.201796476 · Cited by 237 · see citing works
RIPK1 Distinctly Regulates <i>Yersinia</i>-Induced Inflammatory Cell Death, PANoptosis
Malireddi, R. K. S., Kesavardhana, S., Karki, R., Kancharana, B., Burton, A. R., & Kanneganti, T.-D. (2020) · ImmunoHorizons · doi:10.4049/immunohorizons.2000097 · Cited by 224 · see citing works
Lee, E., Song, C.-H., Bae, S.-J., Ha, K.-T., & Karki, R. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-01069-y · Cited by 164 · see citing works
Location, location, location: A compartmentalized view of TNF-induced necroptotic signaling.
Samson, A. L., Garnish, S. E., Hildebrand, J. M., & Murphy, J. M. (2021) · Science Signaling · doi:10.1126/scisignal.abc6178 · Cited by 82 · see citing works
Molecular mechanisms of necroptosis and relevance for neurodegenerative diseases.
(2020) · International Review of Cell and Molecular Biology · doi:10.1016/bs.ircmb.2019.12.006 · Cited by 51 · see citing works
Wang, Z., Feng, J., Yu, J., & Chen, G. (2019) · Journal of Cell Science · doi:10.1242/jcs.227777 · Cited by 35 · see citing works
ZBP1 promotes hepatocyte pyroptosis in acute liver injury by regulating the PGAM5/ROS pathway
Yan, S., Yu, L., Chen, Z., Xie, D., Huang, Z., & Ouyang, S. (2024) · Annals of Hepatology · doi:10.1016/j.aohep.2024.101475 · Cited by 21 · see citing works
- Authors
- Lin, J., Kumari, S., Kim, C., Van, T.-M., Wachsmuth, L., Polykratis, A., & Pasparakis, M.
- Affiliations
- University of Cologne (DE)
- Corresponding author
- Pasparakis, Manolis
- Venue
- Nature
- Published
- 2016-11-07
- Volume
- 540
- Issue
- 7631
- Pages
- 124-128
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5755685
- OpenAlex
- W2547911415
- Cited by
- 421
- References
- 32
- Citations by year
- 2026: 39 · 2025: 63 · 2024: 48 · 2023: 40 · 2022: 42 · 2021: 45 · 2020: 52 · 2019: 33 · 2018: 41 · 2017: 17 · 2016: 1
- FWCI
- 15.85
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Genentech
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- RIPK1, ZBP1, necroptosis, RIPK3, MLKL, skin inflammation, RHIM domain, keratinocytes, perinatal lethality, innate immunity, epidermis, inflammatory skin diseases, DAI, cell death regulation
- MeSH terms
- Protein Domains, Animals, Glycoproteins, Inflammation, Mutation, Necrosis, Phosphorylation, Protein Kinases, Skin, Keratinocytes, RNA-Binding Proteins, Apoptosis, Mice, Receptor-Interacting Protein Serine-Threonine Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
