{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T04:47:23Z","timestamp":1785646043202,"version":"3.56.0"},"reference-count":69,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Prevention and Control of Emerging and Major Infectious Diseases-National Science and Technology Major Project","award":["2026ZD01999704"],"award-info":[{"award-number":["2026ZD01999704"]}]},{"name":"Prevention and Control of Emerging and Major Infectious Diseases-National Science and Technology Major Project","award":["2025ZD01999901"],"award-info":[{"award-number":["2025ZD01999901"]}]},{"name":"Prevention and Control of Emerging and Major Infectious Diseases-National Science and Technology Major Project","award":["2025ZD01902100"],"award-info":[{"award-number":["2025ZD01902100"]}]},{"name":"Major Project of Guangzhou National Laboratory","award":["SRPG22-001"],"award-info":[{"award-number":["SRPG22-001"]}]},{"name":"Major Project of Guangzhou National Laboratory","award":["GZNL2023A01009"],"award-info":[{"award-number":["GZNL2023A01009"]}]},{"award":["SRPG22-001"],"award-info":[{"award-number":["SRPG22-001"]}],"id":[{"id":"https:\/\/ror.org\/03ybmxt82","id-type":"ROR","asserted-by":"publisher"}]},{"award":["GZNL2023A01009"],"award-info":[{"award-number":["GZNL2023A01009"]}],"id":[{"id":"https:\/\/ror.org\/03ybmxt82","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82470003"],"award-info":[{"award-number":["82470003"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82341244"],"award-info":[{"award-number":["82341244"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82271801"],"award-info":[{"award-number":["82271801"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82402059"],"award-info":[{"award-number":["82402059"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82595924"],"award-info":[{"award-number":["82595924"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82502123"],"award-info":[{"award-number":["82502123"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["82470003"],"award-info":[{"award-number":["82470003"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82341244"],"award-info":[{"award-number":["82341244"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82271801"],"award-info":[{"award-number":["82271801"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82402059"],"award-info":[{"award-number":["82402059"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82595924"],"award-info":[{"award-number":["82595924"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82502123"],"award-info":[{"award-number":["82502123"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004608","name":"Natural Science Foundation of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20251921"],"award-info":[{"award-number":["BK20251921"]}],"id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Guangdong High-Level Talent Program","award":["2025TQ09A487"],"award-info":[{"award-number":["2025TQ09A487"]}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFC2306400"],"award-info":[{"award-number":["2023YFC2306400"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Open Research Project of Xiang\u2019an Innovation Laboratory\/National Key Laboratory for Infectious Disease Vaccine Research","award":["2025SKLVDkf03"],"award-info":[{"award-number":["2025SKLVDkf03"]}]},{"name":"2025 Special Project of Basic and Applied Basic Research","award":["2025A04J3556"],"award-info":[{"award-number":["2025A04J3556"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Influenza A virus (IAV) remains a major threat to global public health because of its capacity for antigenic drift, reassortment, zoonotic transmission, and pandemic emergence. Viral transcription and genome replication are carried out by the influenza virus RNA-dependent RNA polymerase (FluPol), a heterotrimeric complex composed of polymerase basic protein 1 (PB1), polymerase basic protein 2 (PB2), and polymerase acidic protein (PA), which functions together with nucleoprotein (NP) within viral ribonucleoprotein complexes (vRNPs). FluPol activity is regulated not only by viral determinants and host cofactors but also by diverse post-translational modifications. Among these, ubiquitination has emerged as a particularly versatile regulatory mechanism because it can control protein stability, polymerase assembly, subunit interactions, conformational dynamics, NP\u2013RNA interactions, and innate immune signaling. Depending on the modified substrate, ubiquitin linkage type, acceptor residue, and responsible E3 ligase or deubiquitinase, ubiquitination may either restrict IAV replication or be exploited by the virus to enhance polymerase function and vRNP activity. This review summarizes recent advances in ubiquitination-mediated regulation of FluPol and NP, focusing on the responsible E3 ubiquitin ligases, deubiquitinases, ubiquitination sites, ubiquitin-chain types, and host restriction mechanisms. We further discuss the crosstalk between ubiquitination and other post-translational modifications, highlight unresolved mechanistic questions, and evaluate the therapeutic potential and challenges of targeting ubiquitin-dependent pathways for antiviral intervention. Collectively, this review provides a conceptual framework for understanding how ubiquitination shapes IAV replication and identifies E3 ligases and DUBs as potential targets for host-directed antiviral strategies.<\/jats:p>","DOI":"10.3390\/microorganisms14081684","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T10:11:38Z","timestamp":1785492698000},"page":"1684","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ubiquitin-Dependent Regulation of Influenza A Virus Polymerase and vRNP Function: Mechanisms and Therapeutic Opportunities"],"prefix":"10.3390","volume":"14","author":[{"given":"Ren","family":"Cao","sequence":"first","affiliation":[{"name":"Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou 510320, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4506-7618","authenticated-orcid":false,"given":"Feng","family":"Guo","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Basic Medical School, Xuzhou Medical University, Xuzhou 221004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"You","family":"Chen","sequence":"additional","affiliation":[{"name":"Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou 510320, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4131-8773","authenticated-orcid":false,"given":"Jinwei","family":"Yuan","sequence":"additional","affiliation":[{"name":"Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou 510320, China"},{"name":"School of Pharmaceutical Sciences, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyang","family":"Fu","sequence":"additional","affiliation":[{"name":"Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou 510320, China"},{"name":"State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3236-5170","authenticated-orcid":false,"given":"Zhongfang","family":"Wang","sequence":"additional","affiliation":[{"name":"Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou 510320, China"},{"name":"State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8342-7637","authenticated-orcid":false,"given":"Donglan","family":"Liu","sequence":"additional","affiliation":[{"name":"Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou 510320, China"},{"name":"State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/nature14460","article-title":"Global circulation patterns of seasonal influenza viruses vary with antigenic drift","volume":"523","author":"Bedford","year":"2015","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Saunders-Hastings, P.R., and Krewski, D. (2016). Reviewing the History of Pandemic Influenza: Understanding Patterns of Emergence and Transmission. Pathogens, 5.","DOI":"10.3390\/pathogens5040066"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.virs.2022.10.005","article-title":"Revisiting influenza A virus life cycle from a perspective of genome balance","volume":"38","author":"Du","year":"2023","journal-title":"Virol. Sin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1111\/irv.12412","article-title":"The ecology and adaptive evolution of influenza A interspecies transmission","volume":"11","author":"Joseph","year":"2017","journal-title":"Influenza Other Respir. Viruses"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.chom.2010.05.009","article-title":"Influenza virus evolution, host adaptation, and pandemic formation","volume":"7","author":"Taubenberger","year":"2010","journal-title":"Cell Host Microbe"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e522","DOI":"10.1016\/S1473-3099(24)00234-2","article-title":"Zoonotic infections by avian influenza virus: Changing global epidemiology, investigation, and control","volume":"24","author":"Kang","year":"2024","journal-title":"Lancet Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/s41579-025-01189-4","article-title":"Evolution, spread and impact of highly pathogenic H5 avian influenza A viruses","volume":"24","author":"Rijnink","year":"2026","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1016\/j.scitotenv.2017.11.226","article-title":"Independent and interactive effects of ambient temperature and absolute humidity on the risks of avian influenza A(H7N9) infection in China","volume":"619\u2013620","author":"Liu","year":"2018","journal-title":"Sci. Total Environ."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.apsb.2025.11.033","article-title":"Anti-influenza drugs targeting trimeric RNA polymerase complex: From development to clinics","volume":"16","author":"Li","year":"2026","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1016\/S1473-3099(16)00078-5","article-title":"Host-directed therapies for infectious diseases: Current status, recent progress, and future prospects","volume":"16","author":"Zumla","year":"2016","journal-title":"Lancet Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"a038398","DOI":"10.1101\/cshperspect.a038398","article-title":"Structure and Function of the Influenza Virus Transcription and Replication Machinery","volume":"10","author":"Fodor","year":"2020","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1038\/nature14008","article-title":"Structure of influenza A polymerase bound to the viral RNA promoter","volume":"516","author":"Pflug","year":"2014","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Hu, J., Zhang, L., and Liu, X. (2020). Role of Post-translational Modifications in Influenza A Virus Life Cycle and Host Innate Immune Response. Front. Microbiol., 11.","DOI":"10.3389\/fmicb.2020.517461"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e00151-11","DOI":"10.1128\/mBio.00151-11","article-title":"Host- and strain-specific regulation of influenza virus polymerase activity by interacting cellular proteins","volume":"2","author":"Bortz","year":"2011","journal-title":"mBio"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Dawson, A.R., and Mehle, A. (2018). Flu\u2019s cues: Exploiting host post-translational modifications to direct the influenza virus replication cycle. PLoS Pathog., 14.","DOI":"10.1371\/journal.ppat.1007205"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1038\/s41586-020-2927-z","article-title":"Host ANP32A mediates the assembly of the influenza virus replicase","volume":"587","author":"Carrique","year":"2020","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nature16474","article-title":"Species difference in ANP32A underlies influenza A virus polymerase host restriction","volume":"529","author":"Long","year":"2016","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Hutchinson, E.C., Denham, E.M., Thomas, B., Trudgian, D.C., Hester, S.S., Ridlova, G., York, A., Turrell, L., and Fodor, E. (2012). Mapping the phosphoproteome of influenza A and B viruses by mass spectrometry. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002993"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7042","DOI":"10.1038\/s41598-023-34285-7","article-title":"Phosphorylation of the PA subunit of influenza polymerase at Y393 prevents binding of the 5\u2032-termini of RNA and polymerase function","volume":"13","author":"Liu","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1038\/s41467-023-36389-0","article-title":"The ubiquitination landscape of the influenza A virus polymerase","volume":"14","author":"Gunl","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Li, J., Liang, L., Jiang, L., Wang, Q., Wen, X., Zhao, Y., Cui, P., Zhang, Y., Wang, G., and Li, Q. (2021). Viral RNA-binding ability conferred by SUMOylation at PB1 K612 of influenza A virus is essential for viral pathogenesis and transmission. PLoS Pathog., 17.","DOI":"10.1371\/journal.ppat.1009336"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Wang, G., Zhao, Y., Zhou, Y., Jiang, L., Liang, L., Kong, F., Yan, Y., Wang, X., Wang, Y., and Wen, X. (2022). PIAS1-mediated SUMOylation of influenza A virus PB2 restricts viral replication and virulence. PLoS Pathog., 18.","DOI":"10.1371\/journal.ppat.1010446"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"43691","DOI":"10.1038\/srep43691","article-title":"NEDDylation of PB2 Reduces Its Stability and Blocks the Replication of Influenza A Virus","volume":"7","author":"Zhang","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"12754","DOI":"10.1038\/ncomms12754","article-title":"Influenza B virus non-structural protein 1 counteracts ISG15 antiviral activity by sequestering ISGylated viral proteins","volume":"7","author":"Zhao","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7126","DOI":"10.1074\/jbc.RA117.001683","article-title":"Influenza A virus nucleoprotein is acetylated by histone acetyltransferases PCAF and GCN5","volume":"293","author":"Hatakeyama","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1038\/s41467-017-01112-3","article-title":"Role of influenza A virus NP acetylation on viral growth and replication","volume":"8","author":"Giese","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/j.celrep.2018.06.078","article-title":"N-Terminal Acetylation by NatB Is Required for the Shutoff Activity of Influenza A Virus PA-X","volume":"24","author":"Oishi","year":"2018","journal-title":"Cell Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1111\/febs.16123","article-title":"Acetylation of the influenza A virus polymerase subunit PA in the N-terminal domain positively regulates its endonuclease activity","volume":"289","author":"Hatakeyama","year":"2022","journal-title":"FEBS J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e0248925","DOI":"10.1128\/mbio.02489-25","article-title":"Delactylation of viral proteins by SIRT1 suppresses influenza A virus replication","volume":"17","author":"Chen","year":"2026","journal-title":"mBio"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e2411554122","DOI":"10.1073\/pnas.2411554122","article-title":"N6-methyladnosine of vRNA facilitates influenza A virus replication by promoting the interaction of vRNA with polymerase proteins","volume":"122","author":"Wang","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e29171","DOI":"10.1002\/jmv.29171","article-title":"Protein arginine methyltransferase 5 mediates arginine symmetric dimethylation of influenza A virus PB2 and supports viral replication","volume":"95","author":"Sun","year":"2023","journal-title":"J. Med. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"14048","DOI":"10.1073\/pnas.1509745112","article-title":"Battle between influenza A virus and a newly identified antiviral activity of the PARP-containing ZAPL protein","volume":"112","author":"Liu","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nrd.2017.152","article-title":"Deubiquitylating enzymes and drug discovery: Emerging opportunities","volume":"17","author":"Harrigan","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.chembiol.2018.10.022","article-title":"From Discovery to Bedside: Targeting the Ubiquitin System","volume":"26","author":"Wertz","year":"2019","journal-title":"Cell Chem. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.cell.2016.03.003","article-title":"Types of Ubiquitin Ligases","volume":"165","author":"Morreale","year":"2016","journal-title":"Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1038\/nature07959","article-title":"Ubiquitylation in innate and adaptive immunity","volume":"458","author":"Bhoj","year":"2009","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/j.cell.2005.11.007","article-title":"A genomic and functional inventory of deubiquitinating enzymes","volume":"123","author":"Nijman","year":"2005","journal-title":"Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1146\/annurev.biochem.78.082307.091526","article-title":"Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes","volume":"78","author":"Ventii","year":"2009","journal-title":"Annu. Rev. Biochem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.molcel.2009.01.014","article-title":"Nonproteolytic functions of ubiquitin in cell signaling","volume":"33","author":"Chen","year":"2009","journal-title":"Mol. Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/cr.2016.39","article-title":"Ubiquitin modifications","volume":"26","author":"Swatek","year":"2016","journal-title":"Cell Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1016\/j.tibs.2025.07.009","article-title":"E3 ubiquitin ligases in signaling, disease, and therapeutics","volume":"50","author":"Ebadi","year":"2025","journal-title":"Trends Biochem. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1146\/annurev-biochem-060310-170328","article-title":"The ubiquitin code","volume":"81","author":"Komander","year":"2012","journal-title":"Annu. Rev. Biochem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1038\/s42003-025-08200-x","article-title":"MYLIP attenuates hypoxia tolerance by inducing K27-linked polyubiquitination and subsequent proteasomal degradation of HIF-alpha","volume":"8","author":"Li","year":"2025","journal-title":"Commun. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e75591","DOI":"10.1002\/advs.75591","article-title":"ZDHHC18-Mediated Palmitoylation of ORF3a Promotes SARS-CoV-2 Pathogenesis by Antagonizing TRIM16-Mediated Ubiquitination and Proteasomal Degradation","volume":"13","author":"Yang","year":"2026","journal-title":"Adv. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"10906","DOI":"10.1128\/JVI.01829-16","article-title":"Ubiquitination Upregulates Influenza Virus Polymerase Function","volume":"90","author":"Kirui","year":"2016","journal-title":"J. Virol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e0033723","DOI":"10.1128\/jvi.00337-23","article-title":"Fine Regulation of Influenza Virus RNA Transcription and Replication by Stoichiometric Changes in Viral NS1 and NS2 Proteins","volume":"97","author":"Zhang","year":"2023","journal-title":"J. Virol."},{"key":"ref_47","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_48","doi-asserted-by":"crossref","first-page":"e0189325","DOI":"10.1128\/jvi.01893-25","article-title":"The viral proteins of influenza A virus competitively bind to TRIM31 with MAVS to fine-tune the antiviral innate immunity","volume":"99","author":"Huang","year":"2025","journal-title":"J. Virol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1007\/s13238-020-00734-6","article-title":"TRIM35 mediates protection against influenza infection by activating TRAF3 and degrading viral PB2","volume":"11","author":"Sun","year":"2020","journal-title":"Protein Cell"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1007\/s11010-020-04006-z","article-title":"Dysfunction of chaperone-mediated autophagy in human diseases","volume":"476","author":"Liao","year":"2021","journal-title":"Mol. Cell. Biochem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1038\/s41580-018-0001-6","article-title":"The coming of age of chaperone-mediated autophagy","volume":"19","author":"Kaushik","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Wang, Y., Jiang, L., Li, Q., Li, M., Shi, W., Wang, B., Wang, G., Deng, G., Shi, J., and Tian, G. (2025). TRIM45 restricts influenza virus infection through modulating the chaperone-mediated autophagic degradation of viral PB2 protein. PLoS Pathog., 21.","DOI":"10.1371\/journal.ppat.1013630"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e00305-20","DOI":"10.1128\/mBio.00305-20","article-title":"Nonproteolytic K29-Linked Ubiquitination of the PB2 Replication Protein of Influenza A Viruses by Proviral Cullin 4-Based E3 Ligases","volume":"11","author":"Karim","year":"2020","journal-title":"mBio"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"100856","DOI":"10.1016\/j.mcpro.2024.100856","article-title":"Profiling Cullin4-E3 Ligases Interactomes and Their Rewiring in Influenza A Virus Infection","volume":"23","author":"Dugied","year":"2024","journal-title":"Mol. Cell. Proteom."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"117002","DOI":"10.1016\/j.celrep.2026.117002","article-title":"Dual roles of USP39 in stabilizing PB2 and orchestrating ribonucleoprotein assembly drive H5 influenza virus replication and pathogenicity","volume":"45","author":"Yang","year":"2026","journal-title":"Cell Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e0013325","DOI":"10.1128\/jvi.00133-25","article-title":"Restriction of influenza A virus replication by host DCAF7-CRL4B axis","volume":"99","author":"Yu","year":"2025","journal-title":"J. Virol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"4523","DOI":"10.1128\/JVI.02548-12","article-title":"TRIM22 inhibits influenza A virus infection by targeting the viral nucleoprotein for degradation","volume":"87","author":"Oteiza","year":"2013","journal-title":"J. Virol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e00905-18","DOI":"10.1128\/JVI.00905-18","article-title":"TRIM41-Mediated Ubiquitination of Nucleoprotein Limits Influenza A Virus Infection","volume":"92","author":"Patil","year":"2018","journal-title":"J. Virol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Wu, X., Wang, J., Wang, S., Wu, F., Chen, Z., Li, C., Cheng, G., and Qin, F.X. (2019). Inhibition of Influenza A Virus Replication by TRIM14 via Its Multifaceted Protein-Protein Interaction with NP. Front. Microbiol., 10.","DOI":"10.3389\/fmicb.2019.00344"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"17242","DOI":"10.1038\/s41598-018-35722-8","article-title":"Grail attenuates influenza A virus infection and pathogenesis by inhibiting viral nucleoprotein","volume":"8","author":"Lin","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2270073","DOI":"10.1080\/22221751.2023.2270073","article-title":"ABTB1 facilitates the replication of influenza A virus by counteracting TRIM4-mediated degradation of viral NP protein","volume":"12","author":"Shi","year":"2023","journal-title":"Emerg. Microbes Infect."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e00597-17","DOI":"10.1128\/mBio.00597-17","article-title":"CNOT4-Mediated Ubiquitination of Influenza A Virus Nucleoprotein Promotes Viral RNA Replication","volume":"8","author":"Lin","year":"2017","journal-title":"mBio"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3879","DOI":"10.1038\/emboj.2010.250","article-title":"Ubiquitination and deubiquitination of NP protein regulates influenza A virus RNA replication","volume":"29","author":"Liao","year":"2010","journal-title":"EMBO J."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"e22537","DOI":"10.1096\/fj.202200473R","article-title":"Pirh2 restricts influenza A virus replication by modulating short-chain ubiquitination of its nucleoprotein","volume":"36","author":"Chen","year":"2022","journal-title":"FASEB J."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1038\/nature05732","article-title":"TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity","volume":"446","author":"Gack","year":"2007","journal-title":"Nature"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/j.chom.2017.10.003","article-title":"Nuclear TRIM25 Specifically Targets Influenza Virus Ribonucleoproteins to Block the Onset of RNA Chain Elongation","volume":"22","author":"Meyerson","year":"2017","journal-title":"Cell Host Microbe"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/s41573-021-00371-6","article-title":"PROTAC targeted protein degraders: The past is prologue","volume":"21","author":"Bekes","year":"2022","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e2518248123","DOI":"10.1073\/pnas.2518248123","article-title":"DeepDegradome: A structure-aware deep learning framework for PROTAC and ligand generation against protein targets","volume":"123","author":"Hu","year":"2026","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/s41392-026-02666-9","article-title":"A nanobody-based proteolysis-targeting chimera offers broad-spectrum protection against diverse influenza virus infections","volume":"11","author":"Zhuang","year":"2026","journal-title":"Signal Transduct. Target. Ther."}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/14\/8\/1684\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T04:26:36Z","timestamp":1785644796000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/14\/8\/1684"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,31]]},"references-count":69,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["microorganisms14081684"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms14081684","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,31]]}}}