PANoptosis is a unique, innate immune, inflammatory, and lytic cell death pathway driven by caspases and RIPKs and regulated by multiprotein PANoptosome complexes.[1][2] The assembly of the PANoptosome cell death complex occurs in response to germline-encoded pattern-recognition receptors (PRRs) sensing pathogens, including bacterial, viral, and fungal infections, as well as pathogen-associated molecular patterns, damage-associated molecular patterns, and cytokines that are released during infections, inflammatory conditions, and cancer.[3][4][5][6][7][8][9][10][11][12][13][14][15][16][1] Several PANoptosome complexes, such as the ZBP1-, AIM2-, RIPK1-, and NLRP12-PANoptosomes, have been characterized so far.[1][17][18][19][20][21]
Emerging genetic, molecular, and biochemical studies have identified extensive crosstalk among the molecular components across various cell death pathways in response to a variety of pathogens and innate immune triggers.[3][4] Historically, inflammatory caspase-mediated pyroptosis and RIPK-driven necroptosis were described as two major inflammatory cell death pathways. While the PANoptosis pathway has some molecular components in common with pyroptosis and necroptosis, as well as with the non-lytic apoptosis pathway, these mechanisms are separate processes that are associated with distinct triggers, protein complexes, and execution pathways.[2] Inflammasome-dependent pyroptosis involves inflammatory caspases, including caspase-1 and caspase-11 in mice, and caspases-1, -4, and -5 in humans, and is executed by gasdermin D.[22][23][24][25][26][27][28] In contrast, necroptosis occurs via RIPK1/3-mediated MLKL activation, which is downstream of caspase-8 inhibition.[29][30][31][32] On the other hand, PANoptosis is [TDK1] driven by caspases and RIPKs and is executed by gasdermins, MLKL, and potentially other yet to be identified molecules cleaved by caspases.[33][34][35][36][37][38][19][21] Moreover, caspase-8 is essential for cell death in PANoptosis[39][40] but needs to be inactivated or inhibited to induce necroptosis.[41][42]
PANoptosis has now been identified in a variety of infections, including viral (influenza A virus, herpes simplex virus 1 (HSV1), coronavirus), bacterial (Yersinia pseudotuberculosis, Francisella novicida), and fungal (Candida albicans, Aspergillus fumigatus). PANoptosis has also been implicated in inflammatory diseases, neurological diseases, and cancer.[43][44][45][46][47][48][49][50][51][52] Activation of PANoptosis can clear infected cells for host defense, and it has shown preclinical promise as an anti-cancer strategy. For example, PANoptosis is important for host defense during influenza infection through the ZBP1-PANoptosome and during Francisella and HSV1 infections through the AIM2-PANoptosome.[5][7][17][19] Additionally, treatment of cancer cells with the PANoptosis-inducing agents TNF and IFN-γ[53][6] can reduce tumor size in preclinical models.[54] The combination of the nuclear export inhibitor selinexor and IFN can also cause PANoptosis and regress tumors in preclinical models.[3][55] However, excess activation of PANoptosis can be associated with inflammation, inflammatory disease, and cytokine storm syndromes.[6][11][56][21][1] Treatments that block TNF and IFN-γ to prevent PANoptosis have provided therapeutic benefit in preclinical models of cytokine storm syndromes, including cytokine shock, SARS-CoV-2 infection, sepsis, and hemophagocytic lymphohistiocytosis, suggesting the therapeutic potential of modulating this pathway.[6][57] Further studies with beta-coronaviruses have shown that IFN can induce ZBP1-mediated PANoptosis during SARS-CoV-2 infection, thereby limiting the efficacy of IFN treatment during infection and resulting in morbidity and mortality. This suggests that inhibiting ZBP1 may improve the therapeutic efficacy of IFN therapy during SARS-CoV-2 infection and possibly other inflammatory conditions where IFN-mediated cell death and pathology occur.[58][59] More recent evidence suggests that NLRP12-mediated PANoptosis is activated by heme, which can be released by red blood cell lysis during infection or inflammatory disease, in combination with specific components of infection or cellular damage. Deletion of NLRP12 protects against pathology in animal models of hemolytic disease, suggesting this could also act as a therapeutic target. Additionally, PANoptosis can also be induced by heat stress (HS), such as fever, during infection, and NINJ1 is a known key executioner in this context. Deletion of NINJ1 in a murine model of HS and infection reduces mortality; furthermore, deleting essential PANoptosis effectors upstream completely rescues the mice from mortality, thereby identifying NINJ1 and PANoptosis effectors as potential therapeutic targets.[60]
The regulation of PANoptosis involves numerous PANoptosomes, which encompass multiple sensor molecules such as NLRP3, ZBP1, AIM2, and NLRP12, along with complex-forming molecules such as caspases and RIPKs. These components activate various downstream cell death executioners and play a role in disease. Therefore, modulating the components of this pathway has potential for therapy.
^ abcd"St. Jude finds NLRP12 as a new drug target for infection, inflammation and hemolytic diseases". www.stjude.org. Retrieved 2024-03-07.
^ abPandeya, Ankit; Kanneganti, Thirumala-Devi (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. ISSN 1471-499X. PMC 10842719. PMID 37977994.
^ abc"Promising preclinical cancer therapy harnesses a newly discovered cell death pathway". www.stjude.org. Retrieved 2021-11-16.
^ ab"ZBP1 links interferon treatment and dangerous inflammatory cell death during COVID-19". www.stjude.org. Retrieved 2022-06-02.
^ ab"The PANoptosome: a new frontier in innate immune responses". www.stjude.org. Retrieved 2021-11-16.
^ abcd"In the lab, St. Jude scientists identify possible COVID-19 treatment". www.stjude.org. Retrieved 2021-11-16.
^ ab"Discovering the secrets of the enigmatic caspase-6". www.stjude.org. Retrieved 2021-11-16.
^"Breaking the dogma: Key cell death regulator has more than one way to get the job done". www.stjude.org. Retrieved 2021-11-16.
^Kuriakose, Teneema; Man, Si Ming; Malireddi, R.K. Subbarao; Karki, Rajendra; Kesavardhana, Sannula; Place, David E.; Neale, Geoffrey; Vogel, Peter; Kanneganti, Thirumala-Devi (2016-08-05). "ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways". Science Immunology. 1 (2): aag2045. doi:10.1126/sciimmunol.aag2045. ISSN 2470-9468. PMC 5131924. PMID 27917412.
^He, Wan-ting; Wan, Haoqiang; Hu, Lichen; Chen, Pengda; Wang, Xin; Huang, Zhe; Yang, Zhang-Hua; Zhong, Chuan-Qi; Han, Jiahuai (December 2015). "Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion". Cell Research. 25 (12): 1285–1298. doi:10.1038/cr.2015.139. ISSN 1748-7838. PMC 4670995. PMID 26611636.
^Aglietti, Robin A.; Estevez, Alberto; Gupta, Aaron; Ramirez, Monica Gonzalez; Liu, Peter S.; Kayagaki, Nobuhiko; Ciferri, Claudio; Dixit, Vishva M.; Dueber, Erin C. (2016-07-12). "GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes". Proceedings of the National Academy of Sciences of the United States of America. 113 (28): 7858–7863. Bibcode:2016PNAS..113.7858A. doi:10.1073/pnas.1607769113. ISSN 1091-6490. PMC 4948338. PMID 27339137.
^Sborgi, Lorenzo; Rühl, Sebastian; Mulvihill, Estefania; Pipercevic, Joka; Heilig, Rosalie; Stahlberg, Henning; Farady, Christopher J.; Müller, Daniel J.; Broz, Petr; Hiller, Sebastian (2016-08-15). "GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death". The EMBO Journal. 35 (16): 1766–1778. doi:10.15252/embj.201694696. ISSN 1460-2075. PMC 5010048. PMID 27418190.
^Martinon, Fabio; Burns, Kimberly; Tschopp, Jürg (July 2002). "The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta". Molecular Cell. 10 (2): 417–426. doi:10.1016/s1097-2765(02)00599-3. ISSN 1097-2765. PMID 12191486.
^Zhao, Jie; Jitkaew, Siriporn; Cai, Zhenyu; Choksi, Swati; Li, Qiuning; Luo, Ji; Liu, Zheng-Gang (2012-04-03). "Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis". Proceedings of the National Academy of Sciences of the United States of America. 109 (14): 5322–5327. Bibcode:2012PNAS..109.5322Z. doi:10.1073/pnas.1200012109. ISSN 1091-6490. PMC 3325682. PMID 22421439.
^Galluzzi, Lorenzo; Kepp, Oliver; Chan, Francis Ka-Ming; Kroemer, Guido (2017-01-24). "Necroptosis: Mechanisms and Relevance to Disease". Annual Review of Pathology. 12: 103–130. doi:10.1146/annurev-pathol-052016-100247. ISSN 1553-4014. PMC 5786374. PMID 27959630.
^Dhuriya, Yogesh K.; Sharma, Divakar (2018-07-06). "Necroptosis: a regulated inflammatory mode of cell death". Journal of Neuroinflammation. 15 (1): 199. doi:10.1186/s12974-018-1235-0. ISSN 1742-2094. PMC 6035417. PMID 29980212.
^Lukens, John R.; Gurung, Prajwal; Vogel, Peter; Johnson, Gordon R.; Carter, Robert A.; McGoldrick, Daniel J.; Bandi, Srinivasa Rao; Calabrese, Christopher R.; Vande Walle, Lieselotte; Lamkanfi, Mohamed; Kanneganti, Thirumala-Devi (2014-12-11). "Dietary modulation of the microbiome affects autoinflammatory disease". Nature. 516 (7530): 246–249. Bibcode:2014Natur.516..246L. doi:10.1038/nature13788. ISSN 1476-4687. PMC 4268032. PMID 25274309.
^Gurung, Prajwal; Burton, Amanda; Kanneganti, Thirumala-Devi (2016-04-19). "NLRP3 inflammasome plays a redundant role with caspase 8 to promote IL-1β-mediated osteomyelitis". Proceedings of the National Academy of Sciences of the United States of America. 113 (16): 4452–4457. doi:10.1073/pnas.1601636113. ISSN 1091-6490. PMC 4843439. PMID 27071119.
^Kuriakose, Teneema; Man, Si Ming; Malireddi, R. K. Subbarao; Karki, Rajendra; Kesavardhana, Sannula; Place, David E.; Neale, Geoffrey; Vogel, Peter; Kanneganti, Thirumala-Devi (2016-08-05). "ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways". Science Immunology. 1 (2): aag2045. doi:10.1126/sciimmunol.aag2045. ISSN 2470-9468. PMC 5131924. PMID 27917412.
^Christgen, Shelbi; Zheng, Min; Kesavardhana, Sannula; Karki, Rajendra; Malireddi, R. K. Subbarao; Banoth, Balaji; Place, David E.; Briard, Benoit; Sharma, Bhesh Raj; Tuladhar, Shraddha; Samir, Parimal; Burton, Amanda; Kanneganti, Thirumala-Devi (2020). "Identification of the PANoptosome: A Molecular Platform Triggering Pyroptosis, Apoptosis, and Necroptosis (PANoptosis)". Frontiers in Cellular and Infection Microbiology. 10: 237. doi:10.3389/fcimb.2020.00237. ISSN 2235-2988. PMC 7274033. PMID 32547960.
^Chen, Wen; Gullett, Jessica M.; Tweedell, Rebecca E.; Kanneganti, Thirumala-Devi (November 2023). "Innate immune inflammatory cell death: PANoptosis and PANoptosomes in host defense and disease". European Journal of Immunology. 53 (11): e2250235. doi:10.1002/eji.202250235. ISSN 1521-4141. PMC 10423303. PMID 36782083.
^Malireddi, R. K. Subbarao; Bynigeri, Ratnakar R.; Mall, Raghvendra; Connelly, Jon P.; Pruett-Miller, Shondra M.; Kanneganti, Thirumala-Devi (2023-10-20). "Inflammatory cell death, PANoptosis, screen identifies host factors in coronavirus innate immune response as therapeutic targets". Communications Biology. 6 (1): 1071. doi:10.1038/s42003-023-05414-9. ISSN 2399-3642. PMC 10589293. PMID 37864059.
^Jiang, Mingxia; Qi, Ling; Li, Lisha; Wu, Yiming; Song, Dongfeng; Li, Yanjing (2021-10-01). "Caspase-8: A key protein of cross-talk signal way in "PANoptosis" in cancer". International Journal of Cancer. 149 (7): 1408–1420. doi:10.1002/ijc.33698. ISSN 1097-0215. PMID 34028029.
^Someda, Masataka; Kuroki, Shunsuke; Miyachi, Hitoshi; Tachibana, Makoto; Yonehara, Shin (May 2020). "Caspase-8, receptor-interacting protein kinase 1 (RIPK1), and RIPK3 regulate retinoic acid-induced cell differentiation and necroptosis". Cell Death and Differentiation. 27 (5): 1539–1553. doi:10.1038/s41418-019-0434-2. ISSN 1476-5403. PMC 7206185. PMID 31659279.
^Rodriguez, Diego A.; Quarato, Giovanni; Liedmann, Swantje; Tummers, Bart; Zhang, Ting; Guy, Cliff; Crawford, Jeremy Chase; Palacios, Gustavo; Pelletier, Stephane; Kalkavan, Halime; Shaw, Jeremy J. P.; Fitzgerald, Patrick; Chen, Mark J.; Balachandran, Siddharth; Green, Douglas R. (2022-10-11). "Caspase-8 and FADD prevent spontaneous ZBP1 expression and necroptosis". Proceedings of the National Academy of Sciences of the United States of America. 119 (41): e2207240119. doi:10.1073/pnas.2207240119. ISSN 1091-6490. PMC 9565532. PMID 36191211.
^Cai, Hantao; Lv, Mingming; Wang, Tingting (December 2023). "PANoptosis in cancer, the triangle of cell death". Cancer Medicine. 12 (24): 22206–22223. doi:10.1002/cam4.6803. ISSN 2045-7634. PMC 10757109. PMID 38069556.
^Malireddi, R. K. Subbarao; Karki, Rajendra; Sundaram, Balamurugan; Kancharana, Balabhaskararao; Lee, SangJoon; Samir, Parimal; Kanneganti, Thirumala-Devi (2021-07-21). "Inflammatory Cell Death, PANoptosis, Mediated by Cytokines in Diverse Cancer Lineages Inhibits Tumor Growth". ImmunoHorizons. 5 (7): 568–580. doi:10.4049/immunohorizons.2100059. ISSN 2573-7732. PMC 8522052. PMID 34290111.
^He, Puxing; Ma, Yixuan; Wu, Yaolu; Zhou, Qing; Du, Huan (2023). "Exploring PANoptosis in breast cancer based on scRNA-seq and bulk-seq". Frontiers in Endocrinology. 14: 1164930. doi:10.3389/fendo.2023.1164930. ISSN 1664-2392. PMC 10338225. PMID 37455906.
^Sun, Yanyan; Zhu, Changlian (February 2023). "Potential role of PANoptosis in neuronal cell death: commentary on "PANoptosis-like cell death in ischemia/reperfusion injury of retinal neurons"". Neural Regeneration Research. 18 (2): 339–340. doi:10.4103/1673-5374.346483. ISSN 1673-5374. PMC 9396522. PMID 35900425.
is essential for cell death in PANoptosis but needs to be inactivated or inhibited to induce necroptosis. PANoptosis has now been identified in a variety...
biological effects in PANoptosis cannot be individually accounted for by pyroptosis, apoptosis, or necroptosis alone. PANoptosis is regulated by multifaceted...
which drive another distinct form of pro-inflammatory cell death called PANoptosis. The germline-encoded PRRs that drive inflammasome formation consist of...
identified roles in programmed cell death such as pyroptosis, necroptosis and PANoptosis. These forms of cell death are important for protecting an organism from...
of inflammatory cell death, which include pyroptosis, necroptosis, and PANoptosis. These cell death pathways help clear infected or aberrant cells and release...
of larger cell death-inducing complexes called PANoptosomes to induce PANoptosis, another inflammatory form of cell death. Activated caspase-1 is responsible...
identified as an innate immune sensor that triggers inflammatory cell death, PANoptosis, and pathology when heme is combined with specific components of cellular...