ZBP1 explained

Z-DNA-binding protein 1, also known as DNA-dependent activator of IFN-regulatory factors (DAI) and DLM-1, is a protein that in humans is encoded by the ZBP1 gene.[1] [2]

ZBP1 is also an abbreviation for chicken or rat β-actin zipcode-binding protein 1, a homolog of the human insulin-like growth factor 2 mRNA-binding protein 1 (IMP-1) and murine CRD-BP, the proteins involved in mRNA transport (RNA-binding proteins, RBPs).

History

ZBP1 was first identified as an interferon-inducible Z-NA binding protein,[3] but its specific functions remained unclear for many years. It was initially thought to be a cytosolic DNA sensor. However, the generation of Zbp1-deficient mice revealed that these mice responded normally to DNA and DNA virus infections, producing normal levels of interferon.[4]

Further insights came with the discovery of ZBP1's receptor-interacting protein homotypic interaction motif (RHIM) domains, which mediate interactions with other proteins. Experiments showed that ZBP1 interacts with RIPK1 and RIPK3 through these RHIM domains.[5] This interaction hinted at ZBP1's involvement in cell death, especially given the role of RIPK proteins in cell death pathways.

The role of ZBP1 as an innate immune sensor became more evident with the discovery that it regulates NLRP3 inflammasome activation and inflammatory cell death, PANoptosis, during influenza A virus infection. ZBP1-deficient mice showed impaired activation of inflammasome components, such as caspase-1, and reduced levels of IL-1β and IL-18, highlighting its critical role in antiviral defense.[6]

Structure

ZBP1 has several key domains that contribute to its function. At the N-terminus, it has Z-nucleic acid (Z-NA) binding domains, known as Zα1 and Zα2. Both Zα domains have a winged helix-turn-helix structure which allows them to bind to Z-RNA/DNA.[7] 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.[8] [9] [10] The C-terminal region of ZBP1 contains a signal domain (SD), which is crucial for triggering an interferon response.[11] [12] [13] [14] [15]

Function and role in disease

ZBP1 was discovered as an innate immune sensor of influenza A virus that forms the ZBP1-PANoptosome to activate the NLRP3 inflammasome and drive cell death, PANoptosis. PANoptosis is a prominent 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.[16] 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 pathogen-associated molecular patterns, damage-associated molecular patterns, cytokines, and homeostatic changes during infections, inflammatory conditions, and cancer.[17] [18] [19] [20] Following the discoveries with IAV, the ZBP1-PANoptosome was also found to play a role in pathogenic inflammation in response to IFN therapy during coronavirus infection.[21]

In contrast, the ZBP1-PANoptosome can have therapeutic benefit in murine tumor models, where IFN and nuclear export inhibitor treatment modulates the ZBP1-ADAR1 pathway and drives ZBP1-PANoptosome formation to regress tumors. Recent research has identified curaxin (CBL0137), a small molecule inhibitor, to effectively induce ZBP1-mediated cell death in cancer-associated fibroblasts and effectively reverse immune checkpoint blockade (ICB) resistance in mouse models of melanoma.[22]

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.[23] ZBP1 has also been extensively implicated in other viral infections, including coronaviruses, cytomegalovirus (CMV),[24] vaccinia (VACV),[25] varicella-zoster virus,[26] zika virus (ZIKV),[27] and others. Furthermore, ZBP1 also induces PANoptosis during Candida albicans and Aspergillus fumigatus infections.[28]

Z-NA binding

ZBP1 is proposed to be a Z-DNA binding protein. Z-DNA formation is a dynamic process, largely controlled by the amount of supercoiling. ZBP1 recognizes DNA in the cytoplasm as an antiviral mechanism. Viral life cycles often include steps where DNA is exposed in the cytoplasm. DNA is normally contained in the nucleus of a cell, and therefore cells use proteins like ZBP1 as an indicator of a viral infection. Once ZBP1 is activated, it increases the production of antiviral cytokines such as interferon beta.[29] DLM1 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).[30]

The role of ZBP1 in DNA sensing has been questioned. It has been found to sense Influenza A Virus (IAV) infection and induce cell death. Since DNA is not synthesized in any stage of IAV life cycle, DNA sensing playing a role in this context is unlikely.[31] [32] However, recent investigation has found that ZBP1 is capable of sensing Z-form RNAs produced during IAV infection, cumulating in a form of caspase independent, inflammatory cell death called necroptosis.[33]

A follow-up study identified that ZBP1 senses the IAV ribonucleoprotein complex to induce cell death. A more recent study has identified transcription factor IRF1 as the upstream regulator of ZBP1 expression.[34]

Further reading

Notes and References

  1. Rothenburg S, Schwartz T, Koch-Nolte F, Haag F . Complex regulation of the human gene for the Z-DNA binding protein DLM-1 . Nucleic Acids Research . 30 . 4 . 993–1000 . February 2002 . 11842111 . 100341 . 10.1093/nar/30.4.993 .
  2. Web site: Entrez Gene: ZBP1 Z-DNA binding protein 1.
  3. Fu Y, Comella N, Tognazzi K, Brown LF, Dvorak HF, Kocher O . Cloning of DLM-1, a novel gene that is up-regulated in activated macrophages, using RNA differential display . Gene . 240 . 1 . 157–163 . November 1999 . 10564822 . 10.1016/s0378-1119(99)00419-9 .
  4. Ishii KJ, Kawagoe T, Koyama S, Matsui K, Kumar H, Kawai T, Uematsu S, Takeuchi O, Takeshita F, Coban C, Akira S . TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines . Nature . 451 . 7179 . 725–729 . February 2008 . 18256672 . 10.1038/nature06537 . 2008Natur.451..725I .
  5. Kaiser WJ, Upton JW, Mocarski ES . 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 . 6427–6434 . November 2008 . 18941233 . 10.4049/jimmunol.181.9.6427 . 3104927 .
  6. Kuriakose T, Man SM, Malireddi RK, Karki R, Kesavardhana S, Place DE, Neale G, Vogel P, Kanneganti TD . ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways . Science Immunology . 1 . 2 . August 2016 . 27917412 . 10.1126/sciimmunol.aag2045 . 5131924 .
  7. Maelfait J, Rehwinkel J . The Z-nucleic acid sensor ZBP1 in health and disease . The Journal of Experimental Medicine . 220 . 8 . e20221156 . August 2023 . 37450010 . 10.1084/jem.20221156 . 10347765 .
  8. Hao Y, Yang B, Yang J, Shi X, Yang X, Zhang D, Zhao D, Yan W, Chen L, Zheng H, Zhang K, Liu X . ZBP1: A Powerful Innate Immune Sensor and Double-Edged Sword in Host Immunity . International Journal of Molecular Sciences . 23 . 18 . 10224 . September 2022 . 36142136 . 10.3390/ijms231810224 . free . 9499459 .
  9. Rebsamen M, Heinz LX, Meylan E, Michallet MC, Schroder K, Hofmann K, Vazquez J, Benedict CA, Tschopp J . DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic interaction motifs to activate NF-kappaB . EMBO Reports . 10 . 8 . 916–922 . August 2009 . 19590578 . 10.1038/embor.2009.109 . 2726668 .
  10. Muendlein HI, Connolly WM, Magri Z, Smirnova I, Ilyukha V, Gautam A, Degterev A, Poltorak A . ZBP1 promotes LPS-induced cell death and IL-1β release via RHIM-mediated interactions with RIPK1 . Nature Communications . 12 . 1 . 86 . January 2021 . 33397971 . 10.1038/s41467-020-20357-z . 7782486 . 2021NatCo..12...86M .
  11. Wang Z, Choi MK, Ban T, Yanai H, Negishi H, Lu Y, Tamura T, Takaoka A, Nishikura K, Taniguchi T . 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 . April 2008 . 18375758 . 2291118 . 10.1073/pnas.0801295105 . free . 2008PNAS..105.5477W .
  12. Szczesny B, Marcatti M, Ahmad A, Montalbano M, Brunyánszki A, Bibli SI, Papapetropoulos A, Szabo C . 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 . January 2018 . 29343810 . 5772643 . 10.1038/s41598-018-19216-1 . 2018NatSR...8..914S .
  13. Rebsamen M, Heinz LX, Meylan E, Michallet MC, Schroder K, Hofmann K, Vazquez J, Benedict CA, Tschopp J . DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic interaction motifs to activate NF-kappaB . EMBO Reports . 10 . 8 . 916–922 . August 2009 . 19590578 . 2726668 . 10.1038/embor.2009.109 .
  14. Schwartz T, Behlke J, Lowenhaupt K, Heinemann U, Rich A . Structure of the DLM-1-Z-DNA complex reveals a conserved family of Z-DNA-binding proteins . Nature Structural Biology . 8 . 9 . 761–765 . September 2001 . 11524677 . 10.1038/nsb0901-761 . 2001-09-01 .
  15. Rothenburg S, Schwartz T, Koch-Nolte F, Haag F . Complex regulation of the human gene for the Z-DNA binding protein DLM-1 . Nucleic Acids Research . 30 . 4 . 993–1000 . February 2002 . 11842111 . 100341 . 10.1093/nar/30.4.993 .
  16. Pandeya A, Kanneganti TD . Therapeutic potential of PANoptosis: innate sensors, inflammasomes, and RIPKs in PANoptosomes . Trends in Molecular Medicine . 30 . 1 . 74–88 . January 2024 . 37977994 . 10.1016/j.molmed.2023.10.001 . 10842719 . January 1, 2025 .
  17. Zheng M, Kanneganti TD . The regulation of the ZBP1-NLRP3 inflammasome and its implications in pyroptosis, apoptosis, and necroptosis (PANoptosis) . Immunological Reviews . 297 . 1 . 26–38 . September 2020 . 32729116 . 7811275 . 10.1111/imr.12909 .
  18. Karki R, Kanneganti TD . ADAR1 and ZBP1 in innate immunity, cell death, and disease . Trends in Immunology . 44 . 3 . 201–216 . March 2023 . 36710220 . 9974732 . 10.1016/j.it.2023.01.001 .
  19. Karki R, Kanneganti TD . PANoptosome signaling and therapeutic implications in infection: central role for ZBP1 to activate the inflammasome and PANoptosis . Current Opinion in Immunology . 83 . 102348 . August 2023 . 37267644 . 10524556 . 10.1016/j.coi.2023.102348 .
  20. Song Q, Qi Z, Wang K, Wang N . Z-nucleic acid sensor ZBP1 in sterile inflammation . Clinical Immunology . Orlando, Fla. . 261 . 109938 . April 2024 . 38346464 . 10.1016/j.clim.2024.109938 .
  21. Karki R, Lee S, Mall R, Pandian N, Wang Y, Sharma BR, Malireddi RS, Yang D, Trifkovic S, Steele JA, Connelly JP, Vishwanath G, Sasikala M, Reddy DN, Vogel P, Pruett-Miller SM, Webby R, Jonsson CB, Kanneganti TD . ZBP1-dependent inflammatory cell death, PANoptosis, and cytokine storm disrupt IFN therapeutic efficacy during coronavirus infection . Science Immunology . 7 . 74 . eabo6294 . August 2022 . 35587515 . 9161373 . 10.1126/sciimmunol.abo6294 .
  22. Zhang T, Yin C, Fedorov A, Qiao L, Bao H, Beknazarov N, Wang S, Gautam A, Williams RM, Crawford JC, Peri S, Studitsky V, Beg AA, Thomas PG, Walkley C, Xu Y, Poptsova M, Herbert A, Balachandran S . ADAR1 masks the cancer immunotherapeutic promise of ZBP1-driven necroptosis . Nature . 606 . 7914 . 594–602 . June 2022 . 35614224 . 9373927 . 10.1038/s41586-022-04753-7 . 2022-05-25 . 2022Natur.606..594Z .
  23. Lee S, Karki R, Wang Y, Nguyen LN, Kalathur RC, Kanneganti TD . AIM2 forms a complex with pyrin and ZBP1 to drive PANoptosis and host defence . Nature . 597 . 7876 . 415–419 . September 2021 . 34471287 . 8603942 . 10.1038/s41586-021-03875-8 . 2021Natur.597..415L .
  24. Upton JW, Kaiser WJ, Mocarski ES . 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 . 564 . October 2019 . 31600504 . 10.1016/j.chom.2019.09.004 . 2019-10-09 .
  25. Koehler H, Cotsmire S, Zhang T, Balachandran S, Upton JW, Langland J, Kalman D, Jacobs BL, Mocarski ES . Vaccinia virus E3 prevents sensing of Z-RNA to block ZBP1-dependent necroptosis . Cell Host & Microbe . 29 . 8 . 1266–1276.e5 . August 2021 . 34192517 . 9333947 . 10.1016/j.chom.2021.05.009 .
  26. Steain M, Baker MO, Pham CL, Shanmugam N, Gambin Y, Sierecki E, McSharry BP, Avdic S, Slobedman B, Sunde M, Abendroth A . Varicella zoster virus encodes a viral decoy RHIM to inhibit cell death . PLOS Pathogens . 16 . 7 . e1008473 . July 2020 . 32649716 . 7375649 . 10.1371/journal.ppat.1008473 . free .
  27. Daniels BP, Kofman SB, Smith JR, Norris GT, Snyder AG, Kolb JP, Gao X, Locasale JW, Martinez J, Gale M, Loo YM, Oberst A . 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 . January 2019 . 30635240 . 6342485 . 10.1016/j.immuni.2018.11.017 .
  28. Banoth B, Tuladhar S, Karki R, Sharma BR, Briard B, Kesavardhana S, Burton A, Kanneganti TD . ZBP1 promotes fungi-induced inflammasome activation and pyroptosis, apoptosis, and necroptosis (PANoptosis) . The Journal of Biological Chemistry . 295 . 52 . 18276–18283 . December 2020 . 33109609 . 7939383 . 10.1074/jbc.RA120.015924 . free .
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  30. Ha SC, Kim D, Hwang HY, Rich A, Kim YG, Kim KK . 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 . December 2008 . 19095800 . 2634953 . 10.1073/pnas.0810463106 . free . 2008PNAS..10520671H .
  31. Kuriakose T, Man SM, Malireddi RK, Karki R, Kesavardhana S, Place DE, Neale G, Vogel P, Kanneganti TD . ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways . Science Immunology . 1 . 2 . aag2045 . August 2016 . 27917412 . 5131924 . 10.1126/sciimmunol.aag2045 .
  32. Kesavardhana S, Kuriakose T, Guy CS, Samir P, Malireddi RK, Mishra A, Kanneganti TD . ZBP1/DAI ubiquitination and sensing of influenza vRNPs activate programmed cell death . The Journal of Experimental Medicine . 214 . 8 . 2217–2229 . August 2017 . 28634194 . 5551577 . 10.1084/jem.20170550 .
  33. Zhang T, Yin C, Boyd DF, Quarato G, Ingram JP, Shubina M, Ragan KB, Ishizuka T, Crawford JC, Tummers B, Rodriguez DA, Xue J, Peri S, Kaiser WJ, López CB, Xu Y, Upton JW, Thomas PG, Green DR, Balachandran S . Influenza Virus Z-RNAs Induce ZBP1-Mediated Necroptosis . Cell . 180 . 6 . 1115–1129.e13 . March 2020 . 32200799 . 7153753 . 10.1016/j.cell.2020.02.050 .
  34. Kuriakose T, Zheng M, Neale G, Kanneganti TD . IRF1 Is a Transcriptional Regulator of ZBP1 Promoting NLRP3 Inflammasome Activation and Cell Death during Influenza Virus Infection . Journal of Immunology . 200 . 4 . 1489–1495 . February 2018 . 29321274 . 6483084 . 10.4049/jimmunol.1701538 .

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