The DOI matches its Crossref record; 14 of the 14 references it cites were found in a registry or an index.
Mlkl knockout mice demonstrate the indispensable role of Mlkl in necroptosis
Open accessAbstract
Mixed lineage kinase domain-like protein (Mlkl) was recently found to interact with receptor interacting protein 3 (Rip3) and to be essential for tumor necrosis factor (TNF)-induced programmed necrosis (necroptosis) in cultured cell lines. We have generated Mlkl-deficient mice by transcription activator-like effector nucleases (TALENs)-mediated gene disruption and found Mlkl to be dispensable for normal mouse development as well as immune cell development. Mlkl-deficient mouse embryonic fibroblasts (MEFs) and macrophages both showed resistance to necrotic but not apoptotic stimuli. Mlkl-deficient MEFs and macrophages were indistinguishable from wild-type cells in their ability to activate NF-κB, ERK, JNK, and p38 in response to TNF and lipopolysaccharides (LPS), respectively. Consistently, Mlkl-deficient macrophages and mice exhibited normal interleukin-1β (IL-1β), IL-6, and TNF production after LPS treatment. Mlkl deficiency protects mice from cerulean-induced acute pancreatitis, a necrosis-related disease, but has no effect on polymicrobial septic shock-induced animal death. Our results provide genetic evidence for the role of Mlkl in necroptosis.
Overview
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
Verification
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.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
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
Self-citationCho, 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
Galluzzi, L., Vitale, I., Abrams, J. M., Alnemri, E. S., Baehrecke, E. H., Blagosklonny, M. V., Dawson, T. M., Dawson, V. L., El-Deiry, W. S., Fulda, S., et al. (2012) · Cell Death & Differentiation · doi:10.1038/cdd.2011.96 · Cited by 2,421
Baines, C. P., Kaiser, R. A., Purcell, N. H., Blair, N. S., Osinska, H., Hambleton, M. A., Brunskill, E. W., Sayen, M. R., Gottlieb, R. A., Dorn, G. W., et al. (2005) · Nature · doi:10.1038/nature03434 · Cited by 2,280
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
RIP3, an Energy Metabolism Regulator That Switches TNF-Induced Cell Death from Apoptosis to Necrosis
Zhang, D.-W., Shao, J., Lin, J., Zhang, N., Lu, B.-J., Lin, S.-C., Dong, M.-Q., & Han, J. (2009) · Science · doi:10.1126/science.1172308 · Cited by 1,931
Self-citationNakagawa, T., Shimizu, S., Watanabe, T., Yamaguchi, O., Otsu, K., Yamagata, H., Inohara, H., Kubo, T., & Tsujimoto, Y. (2005) · Nature · doi:10.1038/nature03317 · Cited by 1,635
Li, J., McQuade, T., Siemer, A. B., Napetschnig, J., Moriwaki, K., Hsiao, Y.-S., Damko, E., Moquin, D., Walz, T., McDermott, A., et al. (2012) · Cell · doi:10.1016/j.cell.2012.06.019 · Cited by 1,222
RIP3 mediates the embryonic lethality of caspase-8-deficient mice
Kaiser, W. J., Upton, J. W., Long, A. B., Livingston-Rosanoff, D., Daley-Bauer, L. P., Hakem, R., Caspary, T., & Mocarski, E. S. (2011) · Nature · doi:10.1038/nature09857 · Cited by 1,057
Cell death by necrosis: towards a molecular definition
Golstein, P., & Kroemer, G. (2007) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2006.11.001 · Cited by 1,044
Research works printed but not linked: 33
- Laster SM, Wood JG, Gooding LR . Tumor necrosis factor can induce both apoptic and necrotic forms of cell lysis. J Immunol 1988; 141:2629–2634. · DOI · Paper page
- Huang Q, Shen HM . To die or to live: the dual role of poly(ADP-ribose) polymerase-1 in autophagy and necrosis under oxidative stress and DNA damage. Autophagy 2009; 5:273–276. · DOI
- Sun H, Wang Y . Novel Ser/Thr protein phosphatases in cell death regulation. Physiology (Bethesda) 2012; 27:43–52.
- Han J, Zhong CQ, Zhang DW . Programmed necrosis: backup to and competitor with apoptosis in the immune system. Nat Immunol 2011; 12:1143–1149. · DOI · Paper page
- Feng S, Yang Y, Mei Y, et al. Cleavage of RIP3 inactivates its caspase-independent apoptosis pathway by removal of kinase domain. Cell Signal 2007; 19:2056–2067. · DOI · Paper page
- Ch'en IL, Tsau JS, Molkentin JD, Komatsu M, Hedrick SM . Mechanisms of necroptosis in T cells. J Exp Med 2011; 208:633–641. · DOI
- Hitomi J, Christofferson DE, Ng A, et al. Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell 2008; 135:1311–1323. · DOI · Paper page
- Duprez L, Takahashi N, Van Hauwermeiren F, et al. RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome. Immunity 2011; 35:908–918. · DOI · Paper page
- Zhu S, Zhang Y, Bai G, Li H . Necrostatin-1 ameliorates symptoms in R6/2 transgenic mouse model of Huntington's disease. Cell Death Dis 2011; 2:e115. · DOI
- Linkermann A, Brasen JH, De Zen F, et al. Dichotomy between RIP1- and RIP3-mediated necroptosis in tumor necrosis factor-alpha-induced shock. Mol Med 2012; 18:577–586. · DOI
- Zhou Z, Han V, Han J . New components of the necroptotic pathway. Protein Cell 2012; 3:811–817. · DOI
- Festjens N, Vanden Berghe T, Vandenabeele P . Necrosis, a well-orchestrated form of cell demise: signalling cascades, important mediators and concomitant immune response. Biochim Biophys Acta 2006; 1757:1371–1387. · DOI · Paper page
- Wallach D, Kang TB, Kovalenko A . The extrinsic cell death pathway and the elan mortel. Cell Death Differ 2008; 15:1533–1541. · DOI
- He S, Liang Y, Shao F, Wang X . Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3-mediated pathway. Proc Natl Acad Sci USA 2011; 108:20054–20059. · DOI · Paper page
- Dunai ZA, Imre G, Barna G, et al. Staurosporine induces necroptotic cell death under caspase-compromised conditions in U937 cells. PLoS One 2012; 7:e41945. · DOI
- Lin J, Li H, Yang M, et al. A role of RIP3-mediated macrophage necrosis in atherosclerosis development. Cell Rep 2013; 3:200–210. · DOI · Paper page
- Zorde-Khvalevsky E, Abramovitch R, Barash H, et al. Toll-like receptor 3 signaling attenuates liver regeneration. Hepatology 2009; 50:198–206. · DOI
- Trichonas G, Murakami Y, Thanos A, et al. Receptor interacting protein kinases mediate retinal detachment-induced photoreceptor necrosis and compensate for inhibition of apoptosis. Proc Natl Acad Sci USA 2010; 107:21695–21700. · DOI · Paper page
- Li Q, Li G, Lan X, et al. Receptor interacting protein 3 suppresses vascular smooth muscle cell growth by inhibition of the phosphoinositide 3-kinase-Akt axis. J Biol Chem 2010; 285:9535–9544. · DOI
- Gunther C, Martini E, Wittkopf N, et al. Caspase-8 regulates TNF-alpha-induced epithelial necroptosis and terminal ileitis. Nature 2011; 477:335–339. · DOI · Paper page
- Sun L, Wang H, Wang Z, et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 2012; 148:213–227. · DOI · Paper page
- Narayan N, Lee IH, Borenstein R, et al. The NAD-dependent deacetylase SIRT2 is required for programmed necrosis. Nature 2012; 492:199–204. · DOI
- Wang Z, Jiang H, Chen S, Du F, Wang X . The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways. Cell 2012; 148:228–243. · DOI · Paper page
- Zhao J, Jitkaew S, Cai Z, et al. Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis. Proc Natl Acad Sci USA 2012; 109:5322–5327. · DOI · Paper page
- Carlson DF, Tan W, Lillico SG, et al. Efficient TALEN-mediated gene knockout in livestock. Proc Natl Acad Sci USA 2012; 109:17382–17387. · DOI · Paper page
- Geurts AM, Cost GJ, Freyvert Y, et al. Knockout rats via embryo microinjection of zinc-finger nucleases. Science 2009; 325:433. · DOI · Paper page
- Mashimo T, Takizawa A, Voigt B, et al. Generation of knockout rats with X-linked severe combined immunodeficiency (X-SCID) using zinc-finger nucleases. PLoS One 2010; 5:e8870. · DOI
- Carbery ID, Ji D, Harrington A, et al. Targeted genome modification in mice using zinc-finger nucleases. Genetics 2010; 186:451–459. · DOI · Paper page
- Zhang DW, Zheng M, Zhao J, et al. Multiple death pathways in TNF-treated fibroblasts: RIP3- and RIP1-dependent and independent routes. Cell Res 2011; 21:368–371. · DOI
- Wang L, Du F, Wang X . TNF-alpha induces two distinct caspase-8 activation pathways. Cell 2008; 133:693–703. · DOI · Paper page
- Newton K, Sun X, Dixit VM . Kinase RIP3 is dispensable for normal NF-kappa Bs, signaling by the B-cell and T-cell receptors, tumor necrosis factor receptor 1, and Toll-like receptors 2 and 4. Mol Cell Biol 2004; 24:1464–1469. · DOI · Paper page
- Pinheiro da Silva F, Nizet V . Cell death during sepsis: integration of disintegration in the inflammatory response to overwhelming infection. Apoptosis 2009; 14:509–521. · DOI
- Gallo KA, Johnson GL . Mixed-lineage kinase control of JNK and p38 MAPK pathways. Nat Rev Mol Cell Biol 2002; 3:663–672. · DOI · Paper page
Cited by
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
Necroptosis and its role in inflammation
Pasparakis, M., & Vandenabeele, P. (2015) · Nature · doi:10.1038/nature14191 · Cited by 2,148
Regulated necrosis: the expanding network of non-apoptotic cell death pathways
Berghe, T. V., Linkermann, A., Jouan-Lanhouet, S., Walczak, H., & Vandenabeele, P. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3737 · Cited by 1,735
Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis
Cai, Z., Jitkaew, S., Zhao, J., Chiang, H.-C., Choksi, S., Liu, J., Ward, Y., Wu, L.-G., & Liu, Z.-G. (2014) · Nature Cell Biology · doi:10.1038/ncb2883 · Cited by 1,322
The Pseudokinase MLKL Mediates Necroptosis via a Molecular Switch Mechanism
Murphy, J. M., Czabotar, P. E., Hildebrand, J. M., Lucet, I. S., Zhang, J.-G., Alvarez-Diaz, S., Lewis, R., Lalaoui, N., Metcalf, D., Webb, A. I., et al. (2013) · Immunity · doi:10.1016/j.immuni.2013.06.018 · Cited by 1,220
Metadata
- Authors
- Wu, J., Huang, Z., Ren, J., Zhang, Z., He, P., Li, Y., Ma, J., Chen, W., Zhang, Y., Zhou, X., Yang, Z., Wu, S.-Q., Chen, L., & Han, J.
- Venue
- Cell Research
- Published
- 2013-07-09
- Volume
- 23
- Issue
- 8
- Pages
- 994-1006
- ISSN
- 1001-0602 (ISSN-L)
- 1748-7838
- OpenAlex
- W2124396497
- Cited by
- 462
- References
- 14
- FWCI
- 19.90
- Type
- journal article
- Language
- en
- Open access
- hybrid
- Licence
- creativecommons.org/licenses/by-nc-nd/3.0 (tdm)
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
How to cite
Cite CoChat for the checks on this page, and the paper for its own findings.
- This page
- CoChat. (2026). Citation check: Mlkl knockout mice demonstrate the indispensable role of Mlkl in necroptosis. https://app.cochat.ai/papers/10.1038/cr.2013.91
- The paper
- Wu, J., Huang, Z., Ren, J., Zhang, Z., He, P., Li, Y., Ma, J., Chen, W., Zhang, Y., Zhou, X., Yang, Z., Wu, S.-Q., Chen, L., & Han, J. (2013). Mlkl knockout mice demonstrate the indispensable role of Mlkl in necroptosis. Cell Research. https://doi.org/10.1038/cr.2013.91
Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.