{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T21:01:49Z","timestamp":1767906109610,"version":"3.49.0"},"reference-count":30,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:00:00Z","timestamp":1759190400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Viruses"],"abstract":"<jats:p>The 14-3-3 protein family, which includes the isoforms \u03b7, \u03b3, \u03b5, \u03b8, \u03b2, and \u03b6, is essential for controlling a number of pathways linked to DNA and RNA viruses, including HIV, influenza A virus (IAV), measles virus, HRSV, and double-stranded DNA viruses. TRIM32, an E3 ubiquitin ligase, has been reported to target IAV\u2019s PB1 polymerase for species-specific degradation via ubiquitination. Notably, 14-3-3\u03b7 binds to phosphorylated TRIM32, preventing its autoubiquitylation and forming soluble but inactive cytoplasmic aggregates that regulate TRIM32 levels. However, the functional link between 14-3-3\u03b7, TRIM32, and PB1 during viral infection remains unclear. In this study, we establish a mechanistic connection between 14-3-3\u03b7\u2013TRIM32 and TRIM32\u2013PB1 interactions in IAV (H1N1) infection. We demonstrate that 14-3-3\u03b7 directly interacts with PB1, influencing viral replication. Using transient knockdown models, we show that 14-3-3\u03b7 deficiency alters influenza virus-induced cytotoxicity, cell death, immune responses, and reactive oxygen species (ROS) production. Additionally, we observe a significant reduction in the soluble TRIM32 levels in 14-3-3\u03b7-deficient cells, which leads to increased PB1 accumulation and thus suggests a critical regulatory role for 14-3-3\u03b7 in PB1 stability. Our findings reveal a novel function of 14-3-3\u03b7 in influenza virus infection, demonstrating its role in PB1 regulation via TRIM32 and its impact on innate immune activation. This study highlights 14-3-3\u03b7 as a possible target for antiviral treatments against influenza and offers fresh insights into the host\u2013virus relationship.<\/jats:p>","DOI":"10.3390\/v17101337","type":"journal-article","created":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T07:58:13Z","timestamp":1759305493000},"page":"1337","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Role of the Chaperone Protein 14-3-3\u03b7 in Regulation of the Infection Dynamics of the Influenza A (H1N1) Virus"],"prefix":"10.3390","volume":"17","author":[{"given":"Debarima","family":"Chatterjee","sequence":"first","affiliation":[{"name":"ICMR-National Institute for Research in Bacterial Infections, Formerly (ICMR-National Institute of Cholera and Enteric Diseases), P33, CIT Road, Scheme XM, Beliaghata, Kolkata 700010, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4712-5460","authenticated-orcid":false,"given":"Partha Pratim","family":"Mondal","sequence":"additional","affiliation":[{"name":"ICMR-National Institute for Research in Bacterial Infections, Formerly (ICMR-National Institute of Cholera and Enteric Diseases), P33, CIT Road, Scheme XM, Beliaghata, Kolkata 700010, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anneshwa","family":"Bhattacharya","sequence":"additional","affiliation":[{"name":"ICMR-National Institute for Research in Bacterial Infections, Formerly (ICMR-National Institute of Cholera and Enteric Diseases), P33, CIT Road, Scheme XM, Beliaghata, Kolkata 700010, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7611-909X","authenticated-orcid":false,"given":"Alok Kumar","family":"Chakrabarti","sequence":"additional","affiliation":[{"name":"ICMR-National Institute for Research in Bacterial Infections, Formerly (ICMR-National Institute of Cholera and Enteric Diseases), P33, CIT Road, Scheme XM, Beliaghata, Kolkata 700010, India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Johnson, K.E.E., Song, T., Greenbaum, B., and Ghedin, E. (2017). Getting the flu: 5 key facts about influenza virus evolution. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006450"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/j.tim.2018.05.013","article-title":"Influenza Virus","volume":"26","author":"Hutchinson","year":"2018","journal-title":"Trends Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Swayne, D.E. (2016). Influenza A virus. Animal Influenza, Wiley. [1st ed.].","DOI":"10.1002\/9781118924341"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Ferl, R.J., Manak, M.S., and Reyes, M.F. (2002). The 14-3-3s. Genome Biol., 3.","DOI":"10.1186\/gb-2002-3-7-reviews3010"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Fu, B., Wang, L., Ding, H., Schwamborn, J.C., Li, S., and Dorf, M.E. (2015). TRIM32 Senses and Restricts Influenza A Virus by Ubiquitination of PB1 Polymerase. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1004960"},{"key":"ref_6","first-page":"2014","article-title":"14-3-3 proteins sequester a pool of soluble TRIM32 ubiquitin ligase to repress autoubiquitination and cytoplasmic body formation","volume":"126","author":"Ichimura","year":"2013","journal-title":"J. Cell Sci."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Cui, Y., Zhang, Y., Dai, S., Wan, S., Guan, H., Wang, D., Jin, B., Xiao, W., and Liu, F. (2024). The mechanism of 14-3-3\u03b7 in thyroxine induced mitophagy in cardiomyocytes. Mol. Cell. Endocrinol., 590.","DOI":"10.1016\/j.mce.2024.112271"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1016\/S0021-9258(17)49923-6","article-title":"The influenza NS1 protein modulates RIG-I activation via a strain-specific direct interaction with the second CARD of RIG-I","volume":"295","author":"Jureka","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Tam, E.-H., Liu, Y.-C., Woung, C.-H., Liu, H.M., Wu, G.-H., Wu, C.-C., Kuo, R.-L., and Jung, J.U. (2021). Role of the Chaperone Protein 14-3-3\u03b5 in the Regulation of Influenza A Virus-Activated Beta Interferon. J. Virol., 95.","DOI":"10.1128\/JVI.00231-21"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.virol.2022.07.002","article-title":"Influenza virus NS1 interacts with 14-3-3\u03b5 to antagonize the production of RIG-I-mediated type I interferons","volume":"574","author":"Wang","year":"2022","journal-title":"Virology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.chom.2019.09.012","article-title":"Zika Virus NS3 Mimics a Cellular 14-3-3-Binding Motif to Antagonize RIG-I- and MDA5-Mediated Innate Immunity","volume":"26","author":"Riedl","year":"2019","journal-title":"Cell Host Microbe"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4173","DOI":"10.1111\/jcmm.16490","article-title":"The role of 14-3-3 proteins in cell signalling pathways and virus infection","volume":"25","author":"Liu","year":"2021","journal-title":"J. Cell. Mol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Lin, J.P., Fan, Y.K., and Liu, H.M. (2019). The 14-3-3\u03b7 chaperone protein promotes antiviral innate immunity via facilitating MDA5 oligomerization and intracellular redistribution. PLoS Pathog., 15.","DOI":"10.1371\/journal.ppat.1007582"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Brentnall, M., Rodriguez-Menocal, L., De Guevara, R.L., Cepero, E., and Boise, L.H. (2013). Caspase-9, caspase-3 and caspase-7 have distinct roles during intrinsic apoptosis. BMC Cell Biol., 14.","DOI":"10.1186\/1471-2121-14-32"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/j.tim.2021.12.011","article-title":"Mitochondria-mediated oxidative stress during viral infection","volume":"30","author":"Foo","year":"2022","journal-title":"Trends Microbiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1002\/cbin.11529","article-title":"Functional damage of endothelial progenitor cells is attenuated by 14-3-3-n through inhibition of mitochondrial injury and oxidative stress","volume":"45","author":"Li","year":"2021","journal-title":"Cell Biol. Int."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Abdrabou, A., Brandwein, D., and Wang, Z. (2020). Differential Subcellular Distribution and Translocation of Seven 14-3-3 Isoforms in Response to EGF and During the Cell Cycle. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21010318"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1128\/JVI.02017-12","article-title":"Influenza Virus Induces Apoptosis via BAD-Mediated Mitochondrial Dysregulation","volume":"87","author":"Tran","year":"2013","journal-title":"J. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2717","DOI":"10.1093\/emboj\/cdg279","article-title":"Caspase 3 activation is essential for efficient influenza virus propagation","volume":"22","author":"Wurzer","year":"2003","journal-title":"EMBO J."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Zeng, Y., Xu, S., Wei, Y., Zhang, X., Wang, Q., Jia, Y., Wang, W., Han, L., Chen, Z., and Wang, Z. (2021). The PB1 protein of influenza A virus inhibits the innate immune response by targeting MAVS for NBR1-mediated selective autophagic degradation. PLoS Pathog., 17.","DOI":"10.1371\/journal.ppat.1009300"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1152\/physrev.00026.2013","article-title":"Mitochondrial Reactive Oxygen Species (ROS) and ROS-Induced ROS Release","volume":"94","author":"Zorov","year":"2014","journal-title":"Physiol. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.cca.2014.05.003","article-title":"Human DExD\/H RNA helicases: Emerging roles in stress survival regulation","volume":"436","author":"Shih","year":"2014","journal-title":"Clin. Chim. Acta"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Brisse, M., and Ly, H. (2019). Comparative Structure and Function Analysis of the RIG-I-Like Receptors: RIG-I and MDA5. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.01586"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.tim.2018.08.007","article-title":"A Balancing Act: MDA5 in Antiviral Immunity and Autoinflammation","volume":"27","author":"Sampaio","year":"2019","journal-title":"Trends Microbiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.bbrc.2008.07.147","article-title":"The mitochondrial antiviral signaling protein, MAVS, is cleaved during apoptosis","volume":"375","author":"Scott","year":"2008","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.molcel.2019.02.013","article-title":"Apoptotic Caspases Suppress Type I Interferon Production via the Cleavage of cGAS, MAVS, and IRF3","volume":"74","author":"Ning","year":"2019","journal-title":"Mol. Cell"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ren, Z., Ding, T., Zuo, Z., Xu, Z., Deng, J., and Wei, Z. (2020). Regulation of MAVS Expression and Signaling Function in the Antiviral Innate Immune Response. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.01030"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4249","DOI":"10.1073\/pnas.061437498","article-title":"14-3-3 protein is a regulator of the mitochondrial and chloroplast ATP synthase","volume":"98","author":"Bunney","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Prajapati, P., Gohel, D., Shinde, A., Roy, M., Singh, K., and Singh, R. (2020). TRIM32 regulates mitochondrial mediated ROS levels and sensitizes the oxidative stress induced cell death. Cell. Signal., 76.","DOI":"10.1016\/j.cellsig.2020.109777"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"7841","DOI":"10.2147\/OTT.S176689","article-title":"TRIM32 overexpression improves chemoresistance through regulation of mitochondrial function in non-small-cell lung cancers","volume":"11","author":"Du","year":"2018","journal-title":"OncoTargets Ther."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/10\/1337\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T04:10:46Z","timestamp":1760587846000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/10\/1337"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,30]]},"references-count":30,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["v17101337"],"URL":"https:\/\/doi.org\/10.3390\/v17101337","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,30]]}}}