ZBP1 promotes fungi-induced inflammasome activation and pyroptosis, apoptosis, and necroptosis (PANoptosis)
Open accessAbstract
Candida albicans and Aspergillus fumigatus are dangerous fungal pathogens with high morbidity and mortality, particularly in immunocompromised patients. Innate immune-mediated programmed cell death (pyroptosis, apoptosis, necroptosis) is an integral part of host defense against pathogens. Inflammasomes, which are canonically formed upstream of pyroptosis, have been characterized as key mediators of fungal sensing and drivers of proinflammatory responses. However, the specific cell death pathways and key upstream sensors activated in the context of Candida and Aspergillus infections are unknown. Here, we report that C. albicans and A. fumigatus infection induced inflammatory programmed cell death in the form of pyroptosis, apoptosis, and necroptosis (PANoptosis). Further, we identified the innate immune sensor Z-DNA binding protein 1 (ZBP1) as the apical sensor of fungal infection responsible for activating the inflammasome/pyroptosis, apoptosis, and necroptosis. The Zα2 domain of ZBP1 was required to promote this inflammasome activation and PANoptosis. Overall, our results demonstrate that C. albicans and A. fumigatus induce PANoptosis and that ZBP1 plays a vital role in inflammasome activation and PANoptosis in response to fungal pathogens.
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?
Cytokines or PAMPs trigger the assembly of a multiprotein complex called the PANoptosome.
“Cytokines or PAMPs trigger the assembly of a multiprotein complex called the PANoptosome.”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [271]
The Discussion says that C. albicans and A. fumigatus activate the ZBP1-PANoptosome, and the paper describes the PANoptosome as a molecular scaffold of interacting proteins. It does not establish that cytokines trigger its assembly; it treats cytokine release as a downstream effect. The Discussion also says fungal PAMPs could potentially be ZBP1 ligands, but whether isolated fungal ligands trigger PANoptosis remains an open question. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe PANoptosome includes various molecules necessary for the activation of downstream programmed cell death (PCD) effectors such as GSDMD, GSDME, CASP3/7, and MLKL.
“This complex includes various molecules necessary for the activation of downstream programmed cell death (PCD) effectors such as GSDMD, GSDME, CASP3/7, and MLKL (Fig. 4).”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [271]
PANoptosis is a united modality of inflammatory programmed cell death, accompanied by markers of apoptosis, necrosis, and pyroptosis pathways.
“PANoptosis, is a united modality of inflammatory programmed cell death, accompanied by markers of apoptosis, necrosis, and pyroptosis pathways.271–275”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [271]
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
Mixed Lineage Kinase Domain-like Protein Mediates Necrosis Signaling Downstream of RIP3 Kinase
Sun, L., Wang, H., Wang, Z., He, S., Chen, S., Liao, D., Wang, L., Yan, J., Liu, W., Lei, X., et al. (2012) · Cell · doi:10.1016/j.cell.2011.11.031 · Cited by 2,698 · see citing works
Non-canonical inflammasome activation targets caspase-11
Kayagaki, N., Warming, S., Lamkanfi, M., Walle, L. V., Louie, S., Dong, J., Newton, K., Qu, Y., Liu, J., Heldens, S., et al. (2011) · Nature · doi:10.1038/nature10558 · Cited by 2,530 · see citing works
Kullberg, B. J., & Arendrup, M. C. (2015) · New England Journal of Medicine · doi:10.1056/nejmra1315399 · Cited by 1,315 · see citing works
Catalytic activity of the caspase-8–FLIPL complex inhibits RIPK3-dependent necrosis
Oberst, A., Dillon, C. P., Weinlich, R., McCormick, L. L., Fitzgerald, P., Pop, C., Hakem, R., Salvesen, G. S., & Green, D. R. (2011) · Nature · doi:10.1038/nature09852 · Cited by 1,278 · cited 1× · see citing works
“WT, Zbp1 (21, 41), Zbp1 (20), Casp1/11 (42), Gsdmd (43), Asc (44), Mlkl (45), Ripk3 (46), Ripk3Casp8 (47), and Casp1/11Ripk3Casp8 (18) mice have been described previously.”
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 · see citing works
Regulation of inflammasome activation
Man, S. M., & Kanneganti, T. (2015) · Immunological Reviews · doi:10.1111/imr.12296 · Cited by 1,071 · see citing works
Self-citationNecroptosis in development, inflammation and disease
Weinlich, R., Oberst, A., Beere, H. M., & Green, D. R. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.149 · Cited by 1,016 · see citing works
Programmed cell death as a defence against infection
Jørgensen, I., Rayamajhi, M., & Miao, E. A. (2017) · Nature reviews. Immunology · doi:10.1038/nri.2016.147 · Cited by 1,014 · see citing works
Caspases in Cell Death, Inflammation, and Pyroptosis
Kesavardhana, S., Malireddi, R. K. S., & Kanneganti, T. (2020) · Annual Review of Immunology · doi:10.1146/annurev-immunol-073119-095439 · Cited by 927 · see citing works
Self-citationRogers, C., Erkes, D. A., Nardone, A., Aplin, A. E., Fernandes‐Alnemri, T., & Alnemri, E. S. (2019) · Nature Communications · doi:10.1038/s41467-019-09397-2 · Cited by 834 · 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
Self-citationUpton, 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
Caspase‐8: regulating life and death
Tummers, B., & Green, D. R. (2017) · Immunological Reviews · doi:10.1111/imr.12541 · Cited by 754 · see citing works
Malireddi, R. K. S., Kesavardhana, S., & Kanneganti, T. (2019) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2019.00406 · Cited by 750 · see citing works
Self-citationSegal, B. H. (2009) · New England Journal of Medicine · doi:10.1056/nejmra0808853 · Cited by 659 · see citing works
RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL
Lawlor, K. E., Khan, N. R., Mildenhall, A., Gerlic, M., Croker, B. A., D’Cruz, A. A., Hall, C. M., Spall, S. K., Anderton, H., Masters, S. L., et al. (2015) · Nature Communications · doi:10.1038/ncomms7282 · Cited by 643 · see citing works
Diverging inflammasome signals in tumorigenesis and potential targeting
Karki, R., & Kanneganti, T. (2019) · Nature reviews. Cancer · doi:10.1038/s41568-019-0123-y · Cited by 641 · see citing works
Self-citationTANK-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
Zheng, M., & Kanneganti, T. (2020) · Immunological Reviews · doi:10.1111/imr.12909 · Cited by 591 · see citing works
Self-citationChristgen, S., Zheng, M., Kesavardhana, S., Karki, R., Malireddi, R. K. S., Banoth, B., Place, D. E., Briard, B., Sharma, B. R., Tuladhar, S., et al. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.00237 · Cited by 588 · see citing works
Self-citationGurung, P., Anand, P., Malireddi, R. K. S., Walle, L. V., Opdenbosch, N. V., Dillon, C. P., Weinlich, R., Green, D. R., Lamkanfi, M., & Kanneganti, T. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1302839 · Cited by 558 · see citing works
Self-citationSamir, 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
Self-citationNewton, 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
Caspase-6 Is a Key Regulator of Innate Immunity, Inflammasome Activation, and Host Defense
Zheng, M., Karki, R., Vogel, P., & Kanneganti, T. (2020) · Cell · doi:10.1016/j.cell.2020.03.040 · Cited by 534 · see citing works
Self-citationZ-nucleic-acid sensing triggers ZBP1-dependent necroptosis and inflammation
Jiao, H., Wachsmuth, L., Kumari, S., Schwarzer, R., Lin, J., Eren, R. O., Fisher, A. D., Lane, R. K., Young, G. R., Kassiotis, G., et al. (2020) · Nature · doi:10.1038/s41586-020-2129-8 · Cited by 493 · see citing works
RIPK1 inhibits ZBP1-driven necroptosis during development
Newton, K., Wickliffe, K. E., Maltzman, A., Dugger, D. L., Strasser, A., Pham, V. C., Lill, J. R., Roose-Girma, M., Warming, S., Solon, M., et al. (2016) · Nature · doi:10.1038/nature20559 · Cited by 390 · see citing works
Malireddi, R. K. S., Gurung, P., Kesavardhana, S., Samir, P., Burton, A. R., Mummareddy, H., Vogel, P., Pelletier, S. W., Burgula, S., & Kanneganti, T. (2019) · The Journal of Experimental Medicine · doi:10.1084/jem.20191644 · Cited by 386 · see citing works
Self-citationDAI/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
Targeted Peptidecentric Proteomics Reveals Caspase-7 as a Substrate of the Caspase-1 Inflammasomes
Lamkanfi, M., Kanneganti, T., Damme, P. V., Berghe, T. V., Vanoverberghe, I., Vandekerckhove, J., Vandenabeele, P., Gevaert, K., & Nuénñez, G. (2008) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m800132-mcp200 · Cited by 341 · see citing works
Self-citationDietary modulation of the microbiome affects autoinflammatory disease
Lukens, J. R., Gurung, P., Vogel, P., Johnson, G. R., Carter, R. A., McGoldrick, D. J., Bandi, S. R., Calabrese, C. R., Walle, L. V., Lamkanfi, M., et al. (2014) · Nature · doi:10.1038/nature13788 · Cited by 314 · see citing works
Self-citationInterferon regulatory factor 1 regulates PANoptosis to prevent colorectal cancer
Karki, R., Sharma, B. R., Lee, E., Banoth, B., Malireddi, R. K. S., Samir, P., Tuladhar, S., Mummareddy, H., Burton, A. R., Vogel, P., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.136720 · Cited by 288 · see citing works
Self-citationKarki, R., Man, S. M., Malireddi, R. K. S., Gurung, P., Vogel, P., Lamkanfi, M., & Kanneganti, T.-D. (2015) · Cell Host & Microbe · doi:10.1016/j.chom.2015.01.006 · Cited by 272 · see citing works
Self-citationTAK1 restricts spontaneous NLRP3 activation and cell death to control myeloid proliferation
Malireddi, R. K. S., Gurung, P., Mavuluri, J., Dasari, T. K., Klco, J. M., Chi, H., & Kanneganti, T. (2018) · The Journal of Experimental Medicine · doi:10.1084/jem.20171922 · Cited by 247 · see citing works
Self-citationZheng, M., Williams, E. P., Malireddi, R. K. S., Karki, R., Banoth, B., Burton, A. R., Webby, R. J., Channappanavar, R., Jonsson, C. B., & Kanneganti, T. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.015036 · Cited by 205 · see citing works
Self-citationZBP1/DAI ubiquitination and sensing of influenza vRNPs activate programmed cell death
Kesavardhana, S., Kuriakose, T., Guy, C. S., Samir, P., Malireddi, R. K. S., Mishra, A., & Kanneganti, T. (2017) · The Journal of Experimental Medicine · doi:10.1084/jem.20170550 · Cited by 193 · see citing works
Self-citationKesavardhana, S., Malireddi, R. K. S., Burton, A. R., Porter, S. N., Vogel, P., Pruett‐Miller, S. M., & Kanneganti, T. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.013752 · Cited by 182 · see citing works
Self-citationIRF8 Regulates Transcription of Naips for NLRC4 Inflammasome Activation
Karki, R., Lee, E., Place, D. E., Samir, P., Mavuluri, J., Sharma, B. R., Balakrishnan, A., Malireddi, R. K. S., Geiger, R., Zhu, Q., et al. (2018) · Cell · doi:10.1016/j.cell.2018.02.055 · Cited by 179 · see citing works
Self-citationÖzören, N., Masumoto, J., Franchi, L., Kanneganti, T., Body–Malapel, M., Ertürk, İ., JAGIRDAR, R. M., Li, Z., Inohara, N., Bertin, J., et al. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.7.4337 · Cited by 172 · see citing works
Self-citationGasdermin D: the long-awaited executioner of pyroptosis
Man, S. M., & Kanneganti, T. (2015) · Cell Research · doi:10.1038/cr.2015.124 · Cited by 154 · see citing works
Self-citationLionakis, M. S., Iliev, I. D., & Hohl, T. M. (2017) · JCI Insight · doi:10.1172/jci.insight.93156 · Cited by 153 · see citing works
Fungal Zymosan and Mannan Activate the Cryopyrin Inflammasome
Lamkanfi, M., Malireddi, R. K. S., & Kanneganti, T. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.023689 · Cited by 147 · see citing works
Self-citationMalireddi, R. K. S., Ippagunta, S. K., Lamkanfi, M., & Kanneganti, T. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1001512 · Cited by 139 · see citing works
Self-citationEmerging issues, challenges, and changing epidemiology of fungal disease outbreaks
Benedict, K., Richardson, M. D., Vallabhaneni, S., Jackson, B. R., & Chiller, T. M. (2017) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(17)30443-7 · Cited by 139 · see citing works
NLRP3 inflammasome plays a redundant role with caspase 8 to promote IL-1β–mediated osteomyelitis
Gurung, P., Burton, A. R., & Kanneganti, T. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1601636113 · Cited by 133 · see citing works
Self-citationCell death–mediated cytokine release and its therapeutic implications
Place, D. E., & Kanneganti, T. (2019) · The Journal of Experimental Medicine · doi:10.1084/jem.20181892 · Cited by 84 · see citing works
Self-citationBriard, B., Karki, R., Malireddi, R. K. S., Bhattacharya, A., Place, D. E., Mavuluri, J., Peters, J. L., Vogel, P., Yamamoto, M., & Kanneganti, T. (2018) · Nature Microbiology · doi:10.1038/s41564-018-0298-0 · Cited by 71 · see citing works
Self-citationAlarmin(g) the innate immune system to invasive fungal infections
Caffrey, A. K., & Obar, J. J. (2016) · Current Opinion in Microbiology · doi:10.1016/j.mib.2016.06.002 · Cited by 22 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
NLRP3 inflammasome activation and cell death
Huang, Y., Xu, W., & Zhou, R. (2021) · Cellular & Molecular Immunology · doi:10.1038/s41423-021-00740-6 · Cited by 1,527 · see citing works
Inflammation and aging: signaling pathways and intervention therapies
Li, X., Li, C., Zhang, W., Wang, Y., Qian, P., & Huang, H. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01502-8 · Cited by 1,443 · 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
Self-citationRIPK1 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
Self-citationLee, 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
Self-citationInflammasome-mediated GSDMD activation facilitates escape of Candida albicans from macrophages
Ding, X., Kambara, H., Guo, R., Kanneganti, A., Acosta-Zaldívar, M., Li, J., Liu, F., Bei, T., Qi, W., Xie, X., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-27034-9 · Cited by 115 · see citing works
Fungal cell wall components modulate our immune system
Briard, B., Fontaine, T., Kanneganti, T.-D., Gow, N. A. R., & Papon, N. (2021) · The Cell Surface · doi:10.1016/j.tcsw.2021.100067 · Cited by 42 · see citing works
Self-citation
- Authors
- Banoth, B., Tuladhar, S., Karki, R., Sharma, B. R., Briard, B., Kesavardhana, S., Burton, A., & Kanneganti, T.-D.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Kanneganti, Thirumala-Devi
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2020-12
- Volume
- 295
- Issue
- 52
- Pages
- 18276-18283
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC7939383
- OpenAlex
- W3096272935
- Cited by
- 237
- References
- 47
- Citations by year
- 2026: 40 · 2025: 61 · 2024: 38 · 2023: 36 · 2022: 42 · 2021: 19 · 2020: 1
- FWCI
- 7.95
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- HHS | National Institutes of Health (AI101935, AI124346, AR056296, CA253095)
- American Lebanese Syrian Associated Charities (N/A)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Keywords
- ZBP1, PANoptosis, pyroptosis, apoptosis, necroptosis, inflammasome activation, Candida albicans, Aspergillus fumigatus, fungal infection, innate immune recognition, programmed cell death
- MeSH terms
- Pyroptosis, Necroptosis, Animals, Fungi, Humans, Inflammation, Macrophages, Mice, Inbred C57BL, RNA-Binding Proteins, Apoptosis, Mice, Inflammasomes
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
