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// Workers AI · dad joke modeDoes ZBP1 bind well? Zip, binding positively, 1.

From Wikipedia, the free encyclopedia

ZBP1
Identifiers
AliasesZBP1, C20orf183, DAI, DLM-1, DLM1, Z-DNA binding protein 1
External IDsOMIM: 606750; MGI: 1927449; GeneCards: ZBP1
Available structures
PDBOrtholog search: PDBe RCSB
Orthologs
DatabasesNCBI: entry; OMA: entry
SpeciesHumanMouse
Entrez

81030

58203

Ensembl

ENSG00000124256

ENSMUSG00000027514

UniProt

Q9H171

Q9QY24

RefSeq (mRNA)

NM_001160417
NM_001160418
NM_001160419
NM_030776
NM_001323966

NM_001139519
NM_021394

RefSeq (protein)

NP_001153889
NP_001153890
NP_001153891
NP_001310895
NP_110403

NP_001132991
NP_067369

Location (UCSC)Chr 20: 57.6 – 57.62 MbChr 2: 173.05 – 173.06 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Z-DNA-binding protein 1 (also known as DNA-dependent activator of IFN-regulatory factors (DAI) and DLM-1) is a mammalian intracellular protein that acts as an innate immune sensor. ZBP1 senses left-handed (Z-form) double-helical Z-DNA and Z-RNA from pathogens (acting as pathogen-associated molecular patterns, PAMPs) or from endogenous sources (acting as damage-associated molecular patterns, DAMPs). ZBP1 associates with receptor-interacting protein kinase 3 (RIPK3) to engage caspases and the NLRP3 inflammasome to form a PANoptosome and initiate PANoptosis, a form of inflammatory programmed cell death.

Z-DNA binding protein 1 should not be confused with β-actin zipcode-binding protein 1 (also known as ZBP1), an alias for the mRNA-binding protein IGF2BP1.

History

[edit]

ZBP1 was first identified as an interferon-inducible Z-NA binding protein,[5] but its specific functions remained unclear for many years. While it was initially thought to be a cytosolic DNA sensor, ZBP1-deficient mice responded normally to DNA and DNA virus infections, producing normal levels of interferon.[6]

Further insights came with the discovery of ZBP1's receptor-interacting protein homotypic interaction motif (RHIM) domains, which mediate interactions with the RHIM domains of other proteins, especially RIPKs.[7] Given the role of RIPK proteins in cell death pathways, these interactions hinted at ZBP1's involvement in cell death.

The role of ZBP1 as an innate immune sensor finally became apparent with the discovery that it regulates NLRP3 inflammasome activation, interleukin-1 cytokine maturation and release, and inflammatory cell death through PANoptosis during influenza A (IAV) virus infection. ZBP1-deficient mice showed impaired activation of inflammasome components such as caspase-1, and reduced levels of IL-1β and IL-18.[8] Since this initial discovery, ZBP1 has been implicated in driving PANoptosis in response to a variety of triggers.[9]

Structure

[edit]

ZBP1 has several key domains that contribute to its function. At the N-terminus, it has Z-nucleic acid (Z-NA) binding domains,[10] known as Zα1 and Zα2. Both Zα domains have a winged helix-turn-helix structure which allows them to bind to Z-RNA/DNA.[11] The intermediate region of ZBP1 contains two receptor-interacting protein homotypic interaction motif (RHIM) domains, RHIM1 and RHIM2, which facilitate interactions with other RHIM domain-containing proteins.[7][12][13][14] The C-terminal region of ZBP1 contains a signal domain (SD), which is crucial for triggering an interferon response.[15][16][13][17][10]

Function and role in disease

[edit]

ZBP1 was discovered as an innate immune sensor of IAV that forms the ZBP1-PANoptosome to activate the NLRP3 inflammasome, driving cell death in the form of PANoptosis. PANoptosis is a distinct innate immune, inflammatory, and lytic cell death pathway initiated by innate immune sensors and driven by caspases and receptor-interacting protein kinases (RIPKs) through PANoptosomes.[18] PANoptosomes are multi-protein complexes assembled by germline-encoded pattern-recognition receptor(s) (PRRs) (innate immune sensor(s)) in response to pathogens, including bacterial, viral, and fungal infections, as well as PAMPs, DAMPs, cytokines, and homeostatic changes during infections, inflammatory conditions, and cancer.[19][20][21][22]

Following the initial discovery of its role as an innate immune sensor of IAV in macrophages and lung cells, ZBP1 was also implicated in driving necroptosis in response to IAV in certain cell types, such as in fibroblasts. Furthermore, the ZBP1-PANoptosome was found to play key roles beyond IAV across multiple cell types. For example, the ZBP1-PANoptosome drives pathogenic inflammation in response to interferon therapy during coronavirus infection.[23] Indeed, the transcription factor interferon response factor 1 (IRF1) is a key upstream regulator of ZBP1 expression.[24] Modulating ZBP1 activity is therefore a potential therapeutic strategy in some viral and inflammatory contexts.

Furthermore, promoting the activity of the ZBP1-PANoptosome can have therapeutic benefit in murine tumor models, where combined interferon and nuclear export inhibitor treatment modulates the ZBP1-ADAR1 pathway and drives ZBP1-PANoptosome formation to regress tumors.[25] Additional research found that curaxin (CBL0137), a small molecule inhibitor, induces ZBP1-mediated cell death in cancer-associated fibroblasts and reverses immune checkpoint blockade (ICB) resistance in mouse models of melanoma.[26]

ZBP1 is also a key component of the absent in melanoma 2 (AIM2)-PANoptosome, which includes the AIM2 inflammasome, and assembles in response to Francisella novicida and herpes simplex virus 1 (HSV1) infections.[27] ZBP1 has also been extensively implicated in other viral infections, including coronaviruses, cytomegalovirus,[28] vaccinia,[29] varicella-zoster virus,[30] zika virus,[31] and others. ZBP1 also induces PANoptosis during Candida albicans and Aspergillus fumigatus infections.[32] It also drives PANoptosis in response to non-microbial triggers, such as ethanol.

Z-DNA and Z-RNA binding

[edit]

ZBP1 is named after its ability to bind Z-DNA. Z-DNA formation is a dynamic process, largely controlled by the amount of supercoiling.[33] ZBP1 has been proposed to sense viruses by recognizing the presence of DNA in the cytoplasm, which occurs in some viral life cycles. Once ZBP1 is activated, it increases the production of antiviral cytokines such as interferon beta.[34] ZBP1 then binds to cytosolic viral DNA using two Z-DNA-binding domains (Zα and Zβ) at its N-terminus along with a DNA binding domain (D3).[35]

The functional importance of DNA in the activation of ZBP1 has been questioned, however. As a negative-strand RNA virus, IAV does not synthesize DNA at any stage of its life cycle. ZBP1 is capable of sensing viral Z-form RNAs such as those produced during IAV infection.[36] Yet, a recent study found that during IAV or HSV-1 infection, ZBP1 predominantly detected host Z-RNAs arising from viral disruption of host transcription termination, not viral Z-NAs.[37]

References

[edit]
  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000124256 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000027514 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Fu Y, Comella N, Tognazzi K, Brown LF, Dvorak HF, Kocher O (November 1999). "Cloning of DLM-1, a novel gene that is up-regulated in activated macrophages, using RNA differential display". Gene. 240 (1): 157–163. doi:10.1016/s0378-1119(99)00419-9. PMID 10564822.
  6. ↑ Ishii KJ, Kawagoe T, Koyama S, Matsui K, Kumar H, Kawai T, et al. (February 2008). "TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines". Nature. 451 (7179): 725–729. Bibcode:2008Natur.451..725I. doi:10.1038/nature06537. PMID 18256672.
  7. 1 2 Kaiser WJ, Upton JW, Mocarski ES (November 2008). "Receptor-interacting protein homotypic interaction motif-dependent control of NF-kappa B activation via the DNA-dependent activator of IFN regulatory factors". Journal of Immunology. 181 (9). Baltimore: 6427–6434. doi:10.4049/jimmunol.181.9.6427. PMC 3104927. PMID 18941233.
  8. ↑ Kuriakose T, Man SM, Malireddi RK, Karki R, Kesavardhana S, Place DE, et al. (August 2016). "ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways". Science Immunology. 1 (2). doi:10.1126/sciimmunol.aag2045. PMC 5131924. PMID 27917412.
  9. ↑ Zengeler KE, Tweedell RE, Kanneganti TD (July 2026). "PANoptosis in life and death across cell types: From innate immunity to therapeutic implications". Cell Chemical Biology. 33 (7): 1021–1037. doi:10.1016/j.chembiol.2026.06.007. PMC 13456057. PMID 42462691.
  10. 1 2 Rothenburg S, Schwartz T, Koch-Nolte F, Haag F (February 2002). "Complex regulation of the human gene for the Z-DNA binding protein DLM-1". Nucleic Acids Research. 30 (4): 993–1000. doi:10.1093/nar/30.4.993. PMC 100341. PMID 11842111.
  11. ↑ Maelfait J, Rehwinkel J (August 2023). "The Z-nucleic acid sensor ZBP1 in health and disease". The Journal of Experimental Medicine. 220 (8) e20221156. doi:10.1084/jem.20221156. PMC 10347765. PMID 37450010.
  12. ↑ Hao Y, Yang B, Yang J, Shi X, Yang X, Zhang D, et al. (September 2022). "ZBP1: A Powerful Innate Immune Sensor and Double-Edged Sword in Host Immunity". International Journal of Molecular Sciences. 23 (18) 10224. doi:10.3390/ijms231810224. PMC 9499459. PMID 36142136.
  13. 1 2 Rebsamen M, Heinz LX, Meylan E, Michallet MC, Schroder K, Hofmann K, et al. (August 2009). "DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic interaction motifs to activate NF-kappaB". EMBO Reports. 10 (8): 916–922. doi:10.1038/embor.2009.109. PMC 2726668. PMID 19590578.
  14. ↑ Muendlein HI, Connolly WM, Magri Z, Smirnova I, Ilyukha V, Gautam A, et al. (January 2021). "ZBP1 promotes LPS-induced cell death and IL-1β release via RHIM-mediated interactions with RIPK1". Nature Communications. 12 (1) 86. Bibcode:2021NatCo..12...86M. doi:10.1038/s41467-020-20357-z. PMC 7782486. PMID 33397971.
  15. ↑ Wang Z, Choi MK, Ban T, Yanai H, Negishi H, Lu Y, et al. (April 2008). "Regulation of innate immune responses by DAI (DLM-1/ZBP1) and other DNA-sensing molecules". Proceedings of the National Academy of Sciences of the United States of America. 105 (14): 5477–5482. Bibcode:2008PNAS..105.5477W. doi:10.1073/pnas.0801295105. PMC 2291118. PMID 18375758.
  16. ↑ Szczesny B, Marcatti M, Ahmad A, Montalbano M, Brunyánszki A, Bibli SI, et al. (January 2018). "Mitochondrial DNA damage and subsequent activation of Z-DNA binding protein 1 links oxidative stress to inflammation in epithelial cells". Scientific Reports. 8 (1) 914. Bibcode:2018NatSR...8..914S. doi:10.1038/s41598-018-19216-1. PMC 5772643. PMID 29343810.
  17. ↑ Schwartz T, Behlke J, Lowenhaupt K, Heinemann U, Rich A (September 2001). "Structure of the DLM-1-Z-DNA complex reveals a conserved family of Z-DNA-binding proteins". Nature Structural Biology. 8 (9) (published 2001-09-01): 761–765. doi:10.1038/nsb0901-761. PMID 11524677.
  18. ↑ Pandeya A, Kanneganti TD (January 2024). "Therapeutic potential of PANoptosis: innate sensors, inflammasomes, and RIPKs in PANoptosomes". Trends in Molecular Medicine. 30 (1): 74–88. doi:10.1016/j.molmed.2023.10.001. PMC 10842719. PMID 37977994.
  19. ↑ Zheng M, Kanneganti TD (September 2020). "The regulation of the ZBP1-NLRP3 inflammasome and its implications in pyroptosis, apoptosis, and necroptosis (PANoptosis)". Immunological Reviews. 297 (1): 26–38. doi:10.1111/imr.12909. PMC 7811275. PMID 32729116.
  20. ↑ Karki R, Kanneganti TD (March 2023). "ADAR1 and ZBP1 in innate immunity, cell death, and disease". Trends in Immunology. 44 (3): 201–216. doi:10.1016/j.it.2023.01.001. PMC 9974732. PMID 36710220.
  21. ↑ Karki R, Kanneganti TD (August 2023). "PANoptosome signaling and therapeutic implications in infection: central role for ZBP1 to activate the inflammasome and PANoptosis". Current Opinion in Immunology. 83 102348. doi:10.1016/j.coi.2023.102348. PMC 10524556. PMID 37267644.
  22. ↑ Song Q, Qi Z, Wang K, Wang N (April 2024). "Z-nucleic acid sensor ZBP1 in sterile inflammation". Clinical Immunology. 261 109938. Orlando, Fla. doi:10.1016/j.clim.2024.109938. PMID 38346464.
  23. ↑ Karki R, Lee S, Mall R, Pandian N, Wang Y, Sharma BR, et al. (August 2022). "ZBP1-dependent inflammatory cell death, PANoptosis, and cytokine storm disrupt IFN therapeutic efficacy during coronavirus infection". Science Immunology. 7 (74) eabo6294. doi:10.1126/sciimmunol.abo6294. PMC 9161373. PMID 35587515.
  24. ↑ Kuriakose T, Zheng M, Neale G, Kanneganti TD (February 2018). "IRF1 Is a Transcriptional Regulator of ZBP1 Promoting NLRP3 Inflammasome Activation and Cell Death during Influenza Virus Infection". Journal of Immunology. 200 (4). Baltimore: 1489–1495. doi:10.4049/jimmunol.1701538. PMC 6483084. PMID 29321274.
  25. ↑ Karki R, Sundaram B, Sharma BR, Lee S, Malireddi RK, Nguyen LN, et al. (October 2021). "ADAR1 restricts ZBP1-mediated immune response and PANoptosis to promote tumorigenesis". Cell Reports. 37 (3) 109858. doi:10.1016/j.celrep.2021.109858. PMC 8853634. PMID 34686350.
  26. ↑ Zhang T, Yin C, Fedorov A, Qiao L, Bao H, Beknazarov N, et al. (June 2022). "ADAR1 masks the cancer immunotherapeutic promise of ZBP1-driven necroptosis". Nature. 606 (7914) (published 2022-05-25): 594–602. Bibcode:2022Natur.606..594Z. doi:10.1038/s41586-022-04753-7. PMC 9373927. PMID 35614224.
  27. ↑ Lee S, Karki R, Wang Y, Nguyen LN, Kalathur RC, Kanneganti TD (September 2021). "AIM2 forms a complex with pyrin and ZBP1 to drive PANoptosis and host defence". Nature. 597 (7876): 415–419. Bibcode:2021Natur.597..415L. doi:10.1038/s41586-021-03875-8. PMC 8603942. PMID 34471287.
  28. ↑ Upton JW, Kaiser WJ, Mocarski ES (October 2019). "DAI/ZBP1/DLM-1 Complexes with RIP3 to Mediate Virus-Induced Programmed Necrosis that Is Targeted by Murine Cytomegalovirus vIRA". Cell Host & Microbe. 26 (4) (published 2019-10-09): 564. doi:10.1016/j.chom.2019.09.004. PMID 31600504.
  29. ↑ Koehler H, Cotsmire S, Zhang T, Balachandran S, Upton JW, Langland J, et al. (August 2021). "Vaccinia virus E3 prevents sensing of Z-RNA to block ZBP1-dependent necroptosis". Cell Host & Microbe. 29 (8): 1266–1276.e5. doi:10.1016/j.chom.2021.05.009. PMC 9333947. PMID 34192517.
  30. ↑ Steain M, Baker MO, Pham CL, Shanmugam N, Gambin Y, Sierecki E, et al. (July 2020). "Varicella zoster virus encodes a viral decoy RHIM to inhibit cell death". PLoS Pathogens. 16 (7) e1008473. doi:10.1371/journal.ppat.1008473. PMC 7375649. PMID 32649716.
  31. ↑ Daniels BP, Kofman SB, Smith JR, Norris GT, Snyder AG, Kolb JP, et al. (January 2019). "The Nucleotide Sensor ZBP1 and Kinase RIPK3 Induce the Enzyme IRG1 to Promote an Antiviral Metabolic State in Neurons". Immunity. 50 (1): 64–76.e4. doi:10.1016/j.immuni.2018.11.017. PMC 6342485. PMID 30635240.
  32. ↑ Banoth B, Tuladhar S, Karki R, Sharma BR, Briard B, Kesavardhana S, et al. (December 2020). "ZBP1 promotes fungi-induced inflammasome activation and pyroptosis, apoptosis, and necroptosis (PANoptosis)". The Journal of Biological Chemistry. 295 (52): 18276–18283. doi:10.1074/jbc.RA120.015924. PMC 7939383. PMID 33109609.
  33. ↑ "Entrez Gene: ZBP1 Z-DNA binding protein 1".
  34. ↑ Rathinam VA, Fitzgerald KA (March 2011). "Innate immune sensing of DNA viruses". Virology. 411 (2): 153–162. doi:10.1016/j.virol.2011.02.003. PMC 3070751. PMID 21334037.
  35. ↑ Ha SC, Kim D, Hwang HY, Rich A, Kim YG, Kim KK (December 2008). "The crystal structure of the second Z-DNA binding domain of human DAI (ZBP1) in complex with Z-DNA reveals an unusual binding mode to Z-DNA". Proceedings of the National Academy of Sciences of the United States of America. 105 (52): 20671–20676. Bibcode:2008PNAS..10520671H. doi:10.1073/pnas.0810463106. PMC 2634953. PMID 19095800.
  36. ↑ Zhang T, Yin C, Boyd DF, Quarato G, Ingram JP, Shubina M, et al. (March 2020). "Influenza Virus Z-RNAs Induce ZBP1-Mediated Necroptosis". Cell. 180 (6): 1115–1129.e13. doi:10.1016/j.cell.2020.02.050. PMC 7153753. PMID 32200799.
  37. ↑ Yin C, Fedorov A, Guo H, Crawford JC, Rousseau C, Zhong X, et al. (December 2025). "Host cell Z-RNAs activate ZBP1 during virus infections". Nature. 648 (8094): 707–716. doi:10.1038/s41586-025-09705-5. PMC 12711578. PMID 41082924.

Further reading

[edit]
  • Ha SC, Van Quyen D, Hwang HY, Oh DB, Brown BA, Lee SM, et al. (February 2006). "Biochemical characterization and preliminary X-ray crystallographic study of the domains of human ZBP1 bound to left-handed Z-DNA". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1764 (2): 320–323. doi:10.1016/j.bbapap.2005.12.012. PMID 16448869.
  • Schwartz T, Rould MA, Lowenhaupt K, Herbert A, Rich A (June 1999). "Crystal structure of the Zalpha domain of the human editing enzyme ADAR1 bound to left-handed Z-DNA". Science. 284 (5421). New York, N.Y.: 1841–1845. doi:10.1126/science.284.5421.1841. PMID 10364558.
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