Journal of Virology最新文献

{"title":"Development and optimization of human T-cell leukemia virus-specific antibody-dependent cell-mediated cytotoxicity (ADCC) assay directed to the envelope protein.","authors":"Cynthia A Pise-Masison, Mohammad Arif Rahman, Daniel C Masison, Anna Gutowska, Ramona Moles, Massimiliano Bissa, Sarkis Sarkis, Luca Schifanella, Tongqing Zhou, Jennifer Jones, Steve Jacobson, Genoveffa Franchini","doi":"10.1128/jvi.02268-24","DOIUrl":"https://doi.org/10.1128/jvi.02268-24","url":null,"abstract":"<p><p>An estimated 10-20 million people worldwide are infected with the deltaretrovirus human T-cell leukemia virus type 1 (HTLV-1). Although most infected individuals remain asymptomatic, some progress to develop the fatal and debilitating disease adult T-cell leukemia/lymphoma (ATLL) or HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) or develop a plethora of other inflammatory disorders. In addition, HTLV-1 infection is associated with immunosuppression and a shorter lifespan. Although a protective role for neutralizing antibodies has been suggested, the role of non-neutralizing antibody-dependent cell-mediated cytotoxicity (ADCC) remains unclear, largely because an assay to measure this response has not been established. Here, we developed a high-throughput flow cytometry-based assay system to measure HTLV-1 envelope-specific ADCC. We used a natural killer cell-resistant T-lymphoblastoid cell line stably expressing the green fluorescent protein GFP to construct a target cell line expressing HTLV-1 envelope protein and using monoclonal antibodies and plasma samples from HTLV-infected or uninfected individuals, validating the specificity and sensitivity of the assay. We detected high ADCC activity in samples from HTLV-1-infected humans. In the plasma of experimentally infected macaques, ADCC activity was measured and a correlation between ADCC activity and HTLV-1 envelope antibody titers was observed. Further, we observed a significant increase in ADCC titer over time; as HTLV-1 infection persists, a higher ADCC response is generated, potentially influencing disease outcome. ADCC titer in HTLV-1-infected macaques also positively correlated with FLT3LG, IL-17F, CD4⁺ T cells, and lymphocytes but negatively correlated with monocyte frequency and classical monocyte frequency. In conclusion, these findings detail the generation of a cell line that enabled development of an HTLV-specific ADCC assay, which can be employed in large clinical studies as well as research involving humans or non-human primates.IMPORTANCEThis approach measures human T-cell leukemia virus (HTLV)-specific envelope antibody-dependent cell-mediated cytotoxicity responses, provides a critical tool to investigate the role of envelope-specific binding antibodies in the immune control of HTLV infection and pathogenesis, and may help guide the development of both therapeutic and preventative vaccine approaches.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0226824"},"PeriodicalIF":4.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of N-linked glycosylation sites in human ACE2 in SARS-CoV-2 and hCoV-NL63 infection.","authors":"Sabrina Noettger, Fabian Zech, Rayhane Nchioua, Chiara Pastorio, Christoph Jung, Timo Jacob, Steffen Stenger, Frank Kirchhoff","doi":"10.1128/jvi.02202-24","DOIUrl":"https://doi.org/10.1128/jvi.02202-24","url":null,"abstract":"<p><p>Angiotensin-converting enzyme 2 (ACE2) is a transmembrane protein known for its physiological role in the renin-angiotensin system that also serves as a receptor for entry of SARS-CoV-1, SARS-CoV-2, and the seasonal human coronavirus NL63 (hCoV-NL63). ACE2 contains seven N-linked glycosylation sites. Molecular simulation and binding analyses suggest that some of them are involved in the interaction with the Spike (S) proteins of hCoVs, but their relevance in S-mediated fusion and viral entry is poorly investigated. To address this, we determined the impact of all seven N-linked glycosylation sites in ACE2 on S-mediated SARS-CoV-2 and hCoV-NL63 infection as well as cell-to-cell fusion. We found that all mutant ACE2 proteins are expressed and localized at the cell surface, albeit ACE2 lacks all glycans at decreased levels. On average, changes in T92I, N322A, and N690A, as well as combined mutation of all N-linked glycosylation sites increased endocytic VSVpp infection mediated by early HU-1 as well as Omicron BA.2, BA.5, and XBB.1.5 SARS-CoV-2 S proteins. In comparison, only the lack of glycan at N322 in ACE2 enhanced syncytia formation and only in the case of HU-1 and XBB.1.5 S proteins. Changes in N90A, T92I, and N322A increased infection by the early SARS-CoV-2 HU-1 strain about twofold to threefold but had lesser effects on infection by genuine Omicron variants. Despite reduced cell surface expression of ACE2, elimination of all N-linked glycosylation sites usually enhanced SARS-CoV-2 infection via the endocytic pathway while having little effect on entry at the cell surface in the presence of TMPRSS2. Our results provide insights into the role of N-linked glycans in the ability of human ACE2 (hACE2) to serve as receptors for coronavirus infection.</p><p><strong>Importance: </strong>Several human coronaviruses use angiotensin-converting enzyme 2 (ACE2) as a primary receptor for infection of human cells. ACE2 is glycosylated at seven distinct positions, and the role of glycans for the entry of SARS-CoV-2 and hCoV-NL63 into their target cells is incompletely understood. Here, we examined the impact of individual and combined mutations in hACE2 glycosylation sites on Spike-mediated VSV-pseudoparticle and genuine SARS-CoV-2 and hCoV-NL63 infection and cell-to-cell fusion. Our results provide new information on the role of glycans in hACE2 for infection by highly pathogenic and seasonal coronaviruses.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0220224"},"PeriodicalIF":4.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A gp41 HR2 residue modulates the susceptibility of HIV-1 envelope glycoproteins to small molecule inhibitors targeting gp120.","authors":"Debashree Chatterjee, Ling Niu, Halima Medjahed, Shilei Ding, Mehdi Benlarbi, Étienne Bélanger, Jérémie Prévost, Hung-Ching Chen, William D Tolbert, Amos B Smith, Marzena Pazgier, Andrés Finzi","doi":"10.1128/jvi.02267-24","DOIUrl":"https://doi.org/10.1128/jvi.02267-24","url":null,"abstract":"<p><p>One characteristic of the HIV-1 CRF01_AE strain is that it contains a bulkier histidine residue at position 375 (H375) in its envelope glycoproteins (Env). This residue is part of the Phe43 cavity, where residue 43 of CD4 engages with gp120. It has been shown that H375 contributes to resistance against small molecule inhibitors targeting gp120. Residue 375 co-evolved with a few residues of the gp120 inner domain layers, and together they modulate the susceptibility of Env to small molecule gp120 inhibitors. Since residue 629 within the HR2 region of gp41 has also been proposed to have co-evolved with residue 375, we explored its role in the susceptibility of HIV-1 Env to two classes of small molecule gp120 inhibitors: the conformational blocker temsavir and the CD4-mimetic (CD4mc) BNM-III-170. Reversion of CRF01_AE isoleucine to a major clade methionine at position 629 had a significant but opposite impact on the susceptibility of the virus to temsavir and BNM-III-170. Mechanistically, this is associated with the capacity of residue 629 to modulate Env stability, as attested by its impact on cold inactivation. Overall, our results show how a single residue of HR2 contributes to the overall Env trimer stability and its susceptibility to gp120-targeted small molecule inhibitors.IMPORTANCECRF01_AE envelope glycoproteins (Env) have a well-conserved histidine at position 375. This residue is key in modulating the susceptibility of HIV-1 to small molecule Env inhibitors. Here, we report that a residue of the gp41 HR2 region affects Env trimer stability and its susceptibility to gp120-directed small molecule inhibitors. This work adds to our understanding of HIV-1 Env resistance to small molecule inhibitors.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0226724"},"PeriodicalIF":4.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143719972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human alpha-herpesvirus 1 (HSV-1) viral replication and reactivation from latency are expedited by the glucocorticoid receptor.","authors":"Clinton Jones","doi":"10.1128/jvi.00303-25","DOIUrl":"https://doi.org/10.1128/jvi.00303-25","url":null,"abstract":"<p><p>Acute human alpha-herpesvirus 1 (HSV-1) infection leads to infection of neurons within trigeminal ganglia (TG), brainstem, and other regions of the central nervous system. Lytic cycle viral gene expression is subsequently silenced, a subset of neurons survive infection, and life-long latency is established. In contrast to lytic infection, the latency-associated transcript (LAT) is the only viral gene product abundantly expressed in latently infected neurons. Stress (acute or chronic), UV light, or heat stress increases the incidence of reactivation from latency in humans and mouse models of infection. Ironically, these divergent reactivation stimuli activate the glucocorticoid receptor (GR). Recent studies revealed GR and Krüppel-like factors (KLF), KLF4 or KLF15 for example, cooperatively transactivate the infected cell protein 0 (ICP0) promoter and cis-regulatory motifs that activate ICP4 and ICP27 promoter activity. GR and KLF4 are \"pioneer transcription factors\" that specifically bind DNA even when it exists as heterochromatin; consequently, chromatin is remodeled, and transcription is activated. Conversely, a VP16 cis-regulatory motif is transactivated by GR and Slug but not KLF family members. Female mice that express a GR containing a serine → alanine mutation at position 229 (GR^S229A) shed significantly lower HSV-1 levels compared with age-matched male GR^S229A mice or wild-type parental C57BL/6 mice during reactivation from latency. These observations imply GR and stress-induced cellular transcription factors play an important role during reactivation from latency by activating key viral promoters. GR activation may also enhance virus spread by impairing immune and inflammatory responses.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0030325"},"PeriodicalIF":4.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143719959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sphingosine-1-phosphate signaling mediates shedding of measles virus-infected respiratory epithelial cells.","authors":"Jacqueline K Brockhurst, Brittany E Salciccioli, Diane E Griffin","doi":"10.1128/jvi.01880-24","DOIUrl":"https://doi.org/10.1128/jvi.01880-24","url":null,"abstract":"<p><p>Measles virus (MeV) is an extremely infectious respiratory virus and a major cause of childhood morbidity and mortality worldwide. MeV infection of the respiratory epithelium induces shedding of multinucleate epithelial cells from the apical surface of the epithelium without compromising epithelial barrier integrity. To study the mechanisms driving the apical extrusion of MeV-infected respiratory epithelial cells, we used primary differentiated tracheal epithelial cell cultures (rhTECs) and respiratory samples from rhesus macaques infected with wild-type MeV (WT MeV) or live-attenuated MeV (LAMV). We show that sphingosine-1-phosphate (S1P) signaling, rather than cell death or inflammasome activation, plays a key role in WT MeV and LAMV-induced cell shedding. Inhibiting S1P signaling resulted in delayed shedding of clusters of infected cells and higher viral titers within the epithelium, suggesting that cell extrusion impacts viral dynamics within the respiratory tract. We also found that shedding of individual infected cells began early after apical infection, prior to the formation of infected cell clusters within the epithelium. These findings offer new insights into MeV biology and pathogenesis within the respiratory tract.</p><p><strong>Importance: </strong>Despite the availability of a safe and effective vaccine, measles virus (MeV) still has a significant global impact, and in 2022 alone led to over 136,000 deaths. MeV is one of the most contagious known viruses and spreads via the respiratory route. When respiratory epithelial cells are infected, they are shed into the lumen of the respiratory tract, but this process is poorly understood. Here, we use primary differentiated respiratory epithelial cells from rhesus macaques to show that sphingosine-1-phosphate (S1P) signaling, and not cell death or inflammasome activation, plays a role in cell shedding during both wild-type and live-attenuated MeV infection. Through this mechanism, MeV-infected cells are extruded without disrupting the integrity of the respiratory epithelium. Inhibiting S1P signaling resulted in delayed shedding of infected cells and higher viral titers in the epithelium. These findings indicate that host cellular responses play an important role in MeV infectivity.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0188024"},"PeriodicalIF":4.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143719607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pseudorabies virus IE180 protein hijacks G3BPs into the nucleus to inhibit stress granule formation.","authors":"Ruihan Zhao, Zhenbang Zhu, Wenqiang Wang, Wei Wen, Zhendong Zhang, Herman W Favoreel, Xiangdong Li","doi":"10.1128/jvi.02088-24","DOIUrl":"https://doi.org/10.1128/jvi.02088-24","url":null,"abstract":"<p><p>Pseudorabies virus (PRV) is a porcine alphaherpesvirus that can infect different animal species and cause pruritus and lethal encephalitis. Stress granules (SGs) are membrane-free cytoplasmic structures formed by liquid-liquid phase separation of G3BP proteins during cell translation inhibition, which generally plays an antiviral role in various viral infections. In this study, we found that infection with different PRV strains inhibits the formation of SGs in host cells. We found that IE180, the only immediate early protein of PRV, has a distinct inhibitory effect on SG formation and colocalizes with SG-nucleating G3BP proteins (G3BP1/2) in the nucleus during PRV infection. Co-immunoprecipitation assays demonstrated an interaction between IE180 and G3BP1/G3BP2, and this interaction appears to depend on the Herpesvirus ICP4-like protein N-terminal (ICP4L-N) domain of IE180 and both NTF2L and RBD domains of G3BP1. Since G3BPs mainly function in the cytoplasm to induce SG formation, we constructed several IE180 protein truncations lacking a nuclear localization sequence to alter the subcellular localization of IE180 to the cytoplasm. Mutant IE180 protein was mainly expressed in the cytoplasm and still suppressed SG formation induced by arsenite or poly(I:C), but its ability to inhibit SG formation was weakened. Importantly, knockout of G3BPs facilitated PRV replication in H1299 cells, while exogenous expression of G3BPs and formation of SGs in wild-type H1299 cells suppressed PRV replication. In summary, our study indicates that PRV IE180 suppresses SG formation and hijacks G3BPs into the nucleus to benefit virus replication.IMPORTANCEHerpesviruses, including pseudorabies virus (PRV), have evolved different strategies to compromise host immune responses. Stress granules (SGs) are one of the targets that viruses can overcome in order to increase replication. The related herpes simplex virus 1 (HSV-1) inhibits SG formation to promote virus replication, but the underlying mechanisms remain unknown. In this study, we confirmed that infection with different PRV strains inhibits SG formation. Interestingly, we found that the PRV immediate early protein IE180 interacts with G3BP proteins and hijacks these proteins into the nucleus to prevent SG formation. In line with the antiviral effect of SGs on PRV replication, exogenous expression of G3BPs and formation of SGs in G3BP1/2 knockout H1299 cells significantly compromised PRV replication. The reported mechanism appears to be also utilized by HSV-1 to prevent SG formation. Therefore, our study elucidates a novel mechanism by which alphaherpesviruses inhibit SG formation, which provides a new perspective to inquire into the immune escape of PRV and other alphaherpesviruses.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0208824"},"PeriodicalIF":4.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143719986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep mutationally scanned CHIKV E3/E2 virus library maps viral amino acid preferences and predicts viral escape mutants of neutralizing CHIKV antibodies.","authors":"Megan M Stumpf, Tonya Brunetti, Bennett J Davenport, Mary K McCarthy, Thomas E Morrison","doi":"10.1128/jvi.00081-25","DOIUrl":"10.1128/jvi.00081-25","url":null,"abstract":"<p><p>As outbreaks of chikungunya virus (CHIKV), a mosquito-borne alphavirus, continue to present public health challenges, additional research is needed to generate protective and safe vaccines and effective therapeutics. Prior research established a role for antibodies in mediating protection against CHIKV infection, and the early appearance of CHIKV-specific IgG or IgG neutralizing antibodies protects against progression to chronic CHIKV disease in humans. However, the importance of epitope specificity for these protective antibodies and how skewed responses contribute to the development of acute and chronic CHIKV-associated joint disease remains poorly understood. Here, we describe the deep mutational scanning of one of the dominant targets of neutralizing antibodies during CHIKV infection, the E3/E2 (also known as p62) glycoprotein complex, to simultaneously test thousands of p62 mutants against selective pressures of interest in a high throughput manner. Characterization of the virus library revealed achievement of high diversity while also selecting out nonfunctional virus variants. Furthermore, this study provides evidence that this virus library system can comprehensively map sites critical for the neutralization function of antibodies of both known and unknown p62 domain specificities.IMPORTANCEChikungunya virus (CHIKV) is a mosquito-borne alphavirus of global health concern that causes debilitating acute and chronic joint disease. Prior studies established a critical role for antibodies in protection against CHIKV infection. Here, we describe the generation of a high-throughput, functional virus library capable of identifying critical functional sites for anti-viral antibodies. This new tool can be used to better understand antibody responses associated with distinct CHIKV infection outcomes and could contribute to the development of efficacious vaccines and antibody-based therapeutics.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0008125"},"PeriodicalIF":4.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143719975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Highly pathogenic avian influenza H5N1: history, current situation, and outlook.","authors":"Florian Krammer, Enikö Hermann, Angela L Rasmussen","doi":"10.1128/jvi.02209-24","DOIUrl":"https://doi.org/10.1128/jvi.02209-24","url":null,"abstract":"<p><p>The H5N1 avian panzootic has resulted in cross-species transmission to birds and mammals, causing outbreaks in wildlife, poultry, and US dairy cattle with a range of host-dependent pathogenic outcomes. Although no human-to-human transmission has been observed, the rising number of zoonotic human cases creates opportunities for adaptive mutation or reassortment. This Gem explores the history, evolution, virology, and epidemiology of clade 2.3.4.4b H5N1 relative to its pandemic potential. Pandemic risk reduction measures are urgently required.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0220924"},"PeriodicalIF":4.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143719977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Restriction of influenza A virus replication by host DCAF7-CRL4B axis.","authors":"Lei Yu, Yong Jiang, Hongyu Rang, Xueyun Wang, Yumeng Cai, Haojie Yan, Shuwen Wu, Ke Lan","doi":"10.1128/jvi.00133-25","DOIUrl":"https://doi.org/10.1128/jvi.00133-25","url":null,"abstract":"<p><p>The balance between cellular defense and viral escape determines the fate of influenza A virus (IAV) infection. Viral polymerase activity is critical for the replication and propagation of IAV. The antiviral strategies of host cells against IAV infection have not been fully elucidated. Here, we identified DCAF7 as an antiviral factor for IAV, which inhibits the replication of H1N1 and H3N2. Mechanistically, DCAF7 weakens the viral heterotrimer polymerase activity and restricts IAV replication and transcription. DCAF7 as a substrate recognition receptor forms a complete CRL4B^DCAF7 E3 ligase with the CRL4B E3 complex to promote K48-linked polyubiquitination of the viral polymerase subunit PA at the K609 site and its degradation. We also showed that a specific cullin-RING E3 ligase (CRL) inhibitor MLN4924 upregulates the protein level of PA and promotes the replication of IAV <i>in vivo</i>. Moreover, activation of CUL4B by etoposide promotes the degradation of PA and inhibits IAV replication <i>in vivo</i>. Importantly, we found that viral NS1 protein decreases DCAF7 level to impair its antiviral efficacy. Taken together, these findings reveal a new mechanism of host resistance to IAV infection and suggest that regulation of the DCAF7-CRL4B axis is a potential target for antivirals.</p><p><strong>Importance: </strong>Until now, the key host factors that affect IAV polymerase have not been fully elucidated. In this study, we identified host DCAF7 as a novel restriction factor for IAV replication. Importantly, DCAF7 acts as a substrate recognition receptor to recruit CRL4B E3 ligase to mediate the degradation of PA through the ubiquitin-proteasome pathway. Further exploration demonstrated that a specific cullin-RING E3 ligase inhibitor MLN4924 promotes IAV replication <i>in vivo</i>, and activation of CUL4B by etoposide inhibits IAV replication <i>in vivo</i>. Notably, we found that the viral NS1 protein decreases DCAF7 level to impair its antiviral efficacy. These findings elucidate the critical function and mechanism of the DCAF7-CRL4B axis in IAV replication, reveal a novel host anti-IAV mechanism, and provide new anti-influenza drug development strategies.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0013325"},"PeriodicalIF":4.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143719996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ZYG11B suppresses multiple enteroviruses by triggering viral VP1 degradation.","authors":"Li Tian, Zhizhong Mi, Weijing Yang, Jing Chen, Xiulong Wei, Wenyan Zhang, Zhaolong Li","doi":"10.1128/jvi.00030-25","DOIUrl":"https://doi.org/10.1128/jvi.00030-25","url":null,"abstract":"<p><p>Enterovirus 71 (EV71) is a major cause of hand, foot, and mouth disease, particularly affecting pediatric populations worldwide. The role of ZYG11B, a CUL2-complex-associated E3 ubiquitin ligase from the Zyg-11 family, in antiviral defense against EV71 remains unclear. To our knowledge, this study is the first to reveal that ZYG11B targets EV71 VP1 for proteasomal degradation via the ubiquitin-proteasome pathway, with CRL2^ZYG11B complex activity specifically driving K33-linked ubiquitination. Mass spectrometry and immunoprecipitation analyses confirmed the interaction between ZYG11B and VP1 and identified key domains required for binding both VP1 and CUL2. Comparative analyses showed that VP1 ubiquitination sites are highly conserved across related enteroviruses, including CA6, CA16, and EVD68. Functional assays further demonstrated that ZYG11B restricts these viruses, highlighting its potential as a broad-spectrum antiviral target. These findings establish ZYG11B as a critical effector in host antiviral responses and support its therapeutic potential for managing enterovirus infections.</p><p><strong>Importance: </strong>E3 ubiquitin ligases and deubiquitinases have become important topics of competition between viruses and hosts. Here, we identified CRL2^ZYG11B as an E3 ubiquitin ligase complex capable of degrading structural protein VP1 of enteroviruses, making ZYG11B a broad-spectrum antiviral factor. We first proposed the inhibitory effect of ZYG11B on viruses and identified the structural domains of ZYG11B connecting substrates and CUL2, providing new targets for the design of antiviral drugs.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0003025"},"PeriodicalIF":4.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}