PLoS Pathogens最新文献

{"title":"Quantifying prevalence and risk factors of HIV multiple infection in Uganda from population-based deep-sequence data.","authors":"Michael A Martin, Andrea Brizzi, Xiaoyue Xi, Ronald Moses Galiwango, Sikhulile Moyo, Deogratius Ssemwanga, Alexandra Blenkinsop, Andrew D Redd, Lucie Abeler-Dörner, Christophe Fraser, Steven J Reynolds, Thomas C Quinn, Joseph Kagaayi, David Bonsall, David Serwadda, Gertrude Nakigozi, Godfrey Kigozi, M Kate Grabowski, Oliver Ratmann","doi":"10.1371/journal.ppat.1013065","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013065","url":null,"abstract":"<p><p>People living with HIV can acquire secondary infections through a process called superinfection, giving rise to simultaneous infection with genetically distinct variants (multiple infection). Multiple infection provides the necessary conditions for the generation of novel recombinant forms of HIV and may worsen clinical outcomes and increase the rate of transmission to HIV seronegative sexual partners. To date, studies of HIV multiple infection have relied on insensitive bulk-sequencing, labor intensive single genome amplification protocols, or deep-sequencing of short genome regions. Here, we identified multiple infections in whole-genome or near whole-genome HIV RNA deep-sequence data generated from plasma samples of 2,029 people living with viremic HIV who participated in the population-based Rakai Community Cohort Study (RCCS). We estimated individual- and population-level probabilities of being multiply infected and assessed epidemiological risk factors using the novel Bayesian deep-phylogenetic multiple infection model (deep - phyloMI) which accounts for bias due to partial sequencing success and false-negative and false-positive detection rates. We estimated that between 2010 and 2020, 4.09% (95% highest posterior density interval (HPD) 2.95%-5.45%) of RCCS participants with viremic HIV multiple infection at time of sampling. Participants living in high-HIV prevalence communities along Lake Victoria were 2.33-fold (95% HPD 1.3-3.7) more likely to harbor a multiple infection compared to individuals in lower prevalence neighboring communities. This work introduces a high-throughput surveillance framework for identifying people with multiple HIV infections and quantifying population-level prevalence and risk factors of multiple infection for clinical and epidemiological investigations.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1013065"},"PeriodicalIF":5.5,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12055032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143994034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bacterial effector screening reveals RNF214 as a virus restriction factor in mammals.","authors":"Aaron Embry, David F Schad, Emily A Rex, Neal M Alto, Don B Gammon","doi":"10.1371/journal.ppat.1013035","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013035","url":null,"abstract":"<p><p>Arboviruses are arthropod-borne viruses that pose significant threats to human and animal health. Previously, we demonstrated that bacterial effector proteins can serve as molecular tools to identify host immunity factors in insect cells that restrict arbovirus replication. In this study, we apply our bacterial effector screening system to identify immunity factors in two mammalian hosts-bats and humans. Our screens identified three bacterial effectors (IpaH4, SopB and SidM) that enhanced the replication of unrelated arboviruses in bat and human cells. We also discovered several effectors that enhanced arbovirus replication in an arbovirus- or host-specific manner. Focusing on the Shigella flexneri-encoded E3 ubiquitin ligase IpaH4, we identified the uncharacterized mammalian really interesting new gene (RING)-domain-containing protein RNF214 as a direct target that is ubiquitinated and degraded by IpaH4. RNF214 belongs to a large family of RING finger (RNF) proteins that primarily function as E3 ubiquitin ligases and that have diverse roles in regulating and mediating innate immune responses to disparate pathogens. Phylogenetic analyses reveal that RNF214 is highly conserved across vertebrate species, suggesting a conserved role in host defense. Functional studies demonstrate that RNF214 overexpression suppresses arbovirus infection in a manner dependent on its putative E3 ubiquitin ligase activity, whereas RNF214 depletion enhances viral replication in both human and bat cells. Furthermore, knockout of RNF214 did not alter the upregulation of interferon (IFN)-stimulated gene expression during infection or upon treatment of cells with IFN. Screening of 11 RNA and DNA viruses, revealed that RNF214 specifically restricts single-stranded RNA (ssRNA) viruses. These findings establish RNF214 as a critical component of the innate immune response against ssRNA viruses that may function independently of the IFN response. More broadly, our work highlights the utility of bacterial effector proteins as powerful tools for uncovering novel antiviral machinery in mammals.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1013035"},"PeriodicalIF":5.5,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12013929/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144051450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA helicases, DDX5 and DDX17, facilitate lytic reactivation of gammaherpesviruses.","authors":"Praneet Kaur Sandhu, Blossom Damania","doi":"10.1371/journal.ppat.1013009","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013009","url":null,"abstract":"<p><p>Human gammaherpesviruses comprise of Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), and are oncogenic viruses that cause life-long infections. The gammaherpesviruses utilize an extensive virus-host interaction network for facilitating viral replication, whereby virus-encoded proteins modulate host processes. Thus, identifying targets of viral proteins that aid in gammaherpesviral replication will help develop therapies to combat these viruses. We identified that host proteins DDX5 and DDX17 interact with gammaherpesviral protein kinases, KSHV-encoded vPK and EBV-encoded BGLF4. We found that DDX5 and DDX17 are required for gammaherpesviral lytic reactivation and loss of both DDX5 and DDX17 decreased KSHV and EBV lytic reactivation. Depletion of DDX5 and DDX17 lowered the transcription of KSHV RTA, the key viral gene that drives the lytic replication cascade, due to reduced occupancy of Brg1, a chromatin remodeler, at the RTA promoter. Consequently, inhibition of Brg1 decreased gammaherpesviral lytic reactivation. Here we demonstrate how gammaherpesviruses hijack the function of two host proteins to promote their lytic replication cycle.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1013009"},"PeriodicalIF":5.5,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12011273/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144020671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Viral piracy of host RNA phosphatase DUSP11 by avipoxviruses.","authors":"Kayla H Szymanik, Emily A Rex, Vamshikrishna R Pothireddy, Don B Gammon, Dustin C Hancks, Christopher S Sullivan","doi":"10.1371/journal.ppat.1013101","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013101","url":null,"abstract":"<p><p>Proper recognition of viral pathogens is an essential part of the innate immune response. A common viral replicative intermediate and chemical signal that cells use to identify pathogens is the presence of a triphosphorylated 5' end (5'ppp) RNA, which activates the cytosolic RNA sensor RIG-I and initiates downstream antiviral signaling. While 5'pppRNA generated by viral RNA-dependent RNA polymerases (RdRps) can be a potent activator of the immune response, endogenous RNA polymerase III (RNAPIII) transcripts can retain the 5'ppp generated during transcription and induce a RIG-I-mediated immune response. We have previously shown that host RNA triphosphatase dual-specificity phosphatase 11 (DUSP11) can act on both host and viral RNAs, altering their levels and reducing their ability to induce RIG-I activation. Our previous work explored how experimentally altered DUSP11 activity can impact immune activation, prompting further exploration into natural contexts of altered DUSP11 activity. Here, we have identified viral DUSP11 homologs (vDUSP11s) present in some avipoxviruses. Consistent with the known functions of host DUSP11, we have shown that expression of vDUSP11s: 1) reduces levels of endogenous RNAPIII transcripts, 2) reduces a cell's sensitivity to 5'pppRNA-mediated immune activation, and 3) restores virus infection defects seen in the absence of DUSP11. Our results identify a context where DUSP11 activity has been co-opted by viruses to alter RNA metabolism and influence the outcome of infection.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1013101"},"PeriodicalIF":5.5,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12058148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144035544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intranasal parainfluenza virus-vectored vaccine expressing SARS-CoV-2 spike protein of Delta or Omicron B.1.1.529 induces mucosal and systemic immunity and protects hamsters against homologous and heterologous challenge.","authors":"Hong-Su Park, Yumiko Matsuoka, Celia Santos, Cindy Luongo, Xueqiao Liu, Lijuan Yang, Jaclyn A Kaiser, Eleanor F Duncan, Reed F Johnson, I-Ting Teng, Peter D Kwong, Ursula J Buchholz, Cyril Le Nouën","doi":"10.1371/journal.ppat.1012585","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012585","url":null,"abstract":"<p><p>The continuous emergence of new SARS-CoV-2 variants requires that COVID vaccines be updated to match circulating strains. We generated B/HPIV3-vectored vaccines expressing 6P-stabilized S protein of the ancestral, B.1.617.2/Delta, or B.1.1.529/Omicron variants as pediatric vaccines for intranasal immunization against HPIV3 and SARS-CoV-2 and characterized these in hamsters. Following intranasal immunization, these B/HPIV3 vectors replicated in the upper and lower respiratory tract and induced mucosal and serum anti-S IgA and IgG. B/HPIV3 expressing ancestral or B.1.617.2/Delta-derived S-6P induced serum antibodies that effectively neutralized SARS-CoV-2 of the ancestral and B.1.617.2/Delta lineages, while the cross-neutralizing potency of B.1.1.529/Omicron S-induced antibodies was lower. Despite the lower cross-neutralizing titers induced by B/HPIV3 expressing S-6P from B.1.1.529/Omicron, a single intranasal dose of all three versions of B/HPIV3 vectors was protective against matched or heterologous WA1/2020, B.1.617.2/Delta or BA.1 (B.1.1.529.1)/Omicron challenge; hamsters were protected from challenge virus replication in the lungs, while low levels of challenge virus were detectable in the upper respiratory tract of a small number of animals. Immunization also protected against lung inflammatory response after challenge, with mild inflammatory cytokine induction associated with the slightly lower level of cross-protection of WA1/2020 and B.1.617.2/Delta variants against the BA.1/Omicron variant. Serum antibodies elicited by all vaccine candidates were broadly reactive against 20 antigenic variants, but the antigenic breadth of antibodies elicited by B/HPIV3-expressed S-6P from the ancestral or B.1.617.2/Delta variant exceeded that of the S-6P B.1.1.529/Omicron expressing vector. These results will guide development of intranasal B/HPIV3 vectors with S antigens matching circulating SARS-CoV-2 variants.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1012585"},"PeriodicalIF":5.5,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12054915/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143989224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expanding kinetoplastid genome annotation through protein structure comparison.","authors":"Juan Manuel Trinidad-Barnech, José Sotelo-Silveira, Darío Fernández Do Porto, Pablo Smircich","doi":"10.1371/journal.ppat.1013120","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013120","url":null,"abstract":"<p><p>Kinetoplastids belong to the Discoba supergroup, an early divergent eukaryotic clade. Although the amount of genomic information on these parasites has grown substantially, assigning gene functions through traditional sequence-based homology methods remains challenging. Recently, significant advancements have been made in in-silico protein structure prediction and algorithms for rapid and precise large-scale protein structure comparisons. In this work, we developed a protein structure-based homology search pipeline (ASC, Annotation by Structural Comparisons) and applied it to transfer biological information to all kinetoplastid proteins available in TriTrypDB, the reference database for this lineage. Our pipeline enabled the assignment of structural similarity to a substantial portion of kinetoplastid proteins, improving current knowledge through annotation transfer. Additionally, we identified structural homologs for representatives of 6,700 uncharacterized proteins across 33 kinetoplastid species, proteins that could not be annotated using existing sequence-based tools and databases. As a result, this approach allowed us to infer potential biological information for a considerable number of kinetoplastid proteins. Among these, we identified structural homologs to ubiquitous eukaryotic proteins that are challenging to detect in kinetoplastid genomes through standard genome annotation pipelines. The results (KASC, Kinetoplastid Annotation by Structural Comparison) are openly accessible to the community at kasc.fcien.edu.uy through a user-friendly, gene-by-gene interface that enables visual inspection of the data.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1013120"},"PeriodicalIF":5.5,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12047770/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144056253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial hyperactivity and reactive oxygen species drive innate immunity to the yellow fever virus-17D live-attenuated vaccine.","authors":"Samantha G Muccilli, Benjamin Schwarz, Byron Shue, Forrest Jessop, Jeffrey G Shannon, Charles L Larson, Adam Hage, Seon-Hui Hong, Eric Bohrnsen, Thomas Hsu, Alison W Ashbrook, Gail L Sturdevant, Shelly J Robertson, Joseph W Guarnieri, Justin Lack, Douglas C Wallace, Catharine M Bosio, Margaret R MacDonald, Charles M Rice, Jonathan W Yewdell, Sonja M Best","doi":"10.1371/journal.ppat.1012561","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012561","url":null,"abstract":"<p><p>The yellow fever virus 17D (YFV-17D) live attenuated vaccine is considered one of the most successful vaccines ever generated associated with high antiviral immunity, yet the signaling mechanisms that drive the response in infected cells are not understood. Here, we provide a molecular understanding of how metabolic stress and innate immune responses are linked to drive type I IFN expression in response to YFV-17D infection. Comparison of YFV-17D replication with its parental virus, YFV-Asibi, and a related dengue virus revealed that IFN expression requires RIG-I-Like Receptor signaling through MAVS, as expected. However, YFV-17D uniquely induces mitochondrial respiration and major metabolic perturbations, including hyperactivation of electron transport to fuel ATP synthase. Mitochondrial hyperactivity generates reactive oxygen species (ROS) including peroxynitrite, blocking of which abrogated MAVS oligomerization and IFN expression in non-immune cells without reducing YFV-17D replication. Scavenging ROS in YFV-17D-infected human dendritic cells increased cell viability yet globally prevented expression of IFN signaling pathways. Thus, adaptation of YFV-17D for high growth imparts mitochondrial hyperactivity to meet energy demands, resulting in generation of ROS as the critical messengers that convert a blunted IFN response into maximal activation of innate immunity essential for vaccine effectiveness.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1012561"},"PeriodicalIF":5.5,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12052391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144055347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The molecular basis for DNA-binding by competence T4P is distinct in a representative Gram-positive and Gram-negative species.","authors":"Nicholas D Christman, Ankur B Dalia","doi":"10.1371/journal.ppat.1013128","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013128","url":null,"abstract":"<p><p>Competence type IV pili (T4P) are bacterial surface appendages that facilitate DNA uptake during horizontal gene transfer by natural transformation. These dynamic structures actively extend from the cell surface, bind to DNA in the environment, and then retract to import bound DNA into the cell. Competence T4P are found in diverse Gram-negative (diderm) and Gram-positive (monoderm) bacterial species. While the mechanism of DNA-binding by diderm competence T4P has been the recent focus of intensive study, relatively little is known about DNA-binding by monoderm competence T4P. Here, we use Streptococcus pneumoniae as a model system to address this question. Competence T4P likely bind to DNA via a tip-associated complex of proteins called minor pilins, and recent work highlights a high degree of structural conservation between the minor pilin tip complexes of monoderm and diderm competence T4P. In diderms, positively charged residues in one minor pilin, FimT, are critical for DNA-binding. We show that while these residues are conserved in ComGD, the FimT homolog of monoderms, they only play a minor role in DNA uptake for natural transformation. Instead, we find that two-positively charged residues in the neighboring minor pilin, ComGF (the PilW homolog of monoderms), play the dominant role in DNA uptake for natural transformation. Furthermore, we find that these residues are conserved in other monoderms, but not diderms. Together, these results suggest that the molecular basis for DNA-binding has either diverged or evolved independently in monoderm and diderm competence T4P.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1013128"},"PeriodicalIF":5.5,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12040237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144023387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activity-based protein profiling reveals both canonical and novel ubiquitin pathway enzymes in Plasmodium.","authors":"Cameron Smith, Mohsen Hajisadeghian, Gerbrand J van der Heden van Noort, Michael J Deery, Adán Pinto-Fernández, Benedikt M Kessler, Katerina Artavanis-Tsakonas","doi":"10.1371/journal.ppat.1013032","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013032","url":null,"abstract":"<p><p>The ubiquitin-proteasome system (UPS) is essential for Plasmodium falciparum survival and represents a potential target for antimalarial therapies. We utilised a ubiquitin- activity based probe (Ub-Dha) to capture active components of the ubiquitin conjugating machinery during asexual blood-stage development. Several E2 ubiquitin-conjugating enzymes, the E1 activating enzyme, and the HECT E3 ligase PfHEUL were identified and validated through in vitro ubiquitination assays. We also demonstrate selective functional interactions between PfHEUL and a subset of both human and P. falciparum E2s. Additionally, the Ub-Dha probe captured an uncharacterized protein, PF3D7_0811400 (C0H4U0) with no known homology to ubiquitin-pathway enzymes in other organisms. Through structural and biochemical analysis, we validate it as a novel E2 enzyme, capable of binding ubiquitin in a cysteine-specific manner. These findings contribute to our understanding of the P. falciparum UPS, identifying promising novel drug targets and highlighting the evolutionary uniqueness of the Ub-proteasome system in this parasite.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1013032"},"PeriodicalIF":5.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12007708/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143992305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNF149 modulates the type I IFN innate antiviral immune responses through degrading IRF3.","authors":"Mengyun Wu, Jiamin Cai, Guodong Qiao, Xiaoping Li, Ji Zhou, Fei Xu, Yunfei Ye, Yufeng Wang, Xuena Xu, Jiaoyang Li, Xiaoyu Tian, Yu Shao, Chunsheng Dong, Zhengrong Chen, Chuangli Hao, Yi Yang, Jinping Zhang","doi":"10.1371/journal.ppat.1013051","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013051","url":null,"abstract":"<p><p>E3 ubiquitin ligases are key molecules in regulating the innate immune responses against virus. They catalyze the activation or degradation of various signaling proteins involved in the innate immune responses. Herein, we found the regulatory role of RNF149 in the host's innate immune responses against viral infection. Virus infection induced the expression of RNF149. Overexpression of RNF149 was associated with reduced production of IFN-β and enhanced viral replication. Mechanically, RNF149 interacted with IRF3 and downregulated its protein level. As an E3 ubiquitin ligase, RNF149 promoted the K27-linked ubiquitination of IRF3 at K409 and K33-linked ubiquitination at K366 and K409, which promoted IRF3 degradation through the proteasome pathway. Our results revealed the regulatory mechanism of RNF149 during viral infection and provided new insights into host cells responding to viral infection. Downregulating the expression of RNF149 may help enhance the antiviral ability of host cells and inhibit viral replication, thus providing a new strategy for the treatment of viral infection.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1013051"},"PeriodicalIF":5.5,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12005527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143994051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}