Journal of Virology最新文献

{"title":"The effective multiplicity of infection for HCMV depends on the activity of the cellular 20S proteasome.","authors":"Katie M Cataldo, Kathryn L Roche, Christopher E Monti, Ranjan K Dash, Eain A Murphy, Scott S Terhune","doi":"10.1128/jvi.01751-24","DOIUrl":"10.1128/jvi.01751-24","url":null,"abstract":"<p><p>Human cytomegalovirus (HCMV) is a betaherpesvirus capable of infecting numerous cell types and persisting throughout an infected individual's life. Disease usually occurs in individuals with compromised or underdeveloped immune systems. Several antivirals exist but have limitations relating to toxicity and resistance. HCMV replication involves upregulation of host proteasomal activities, which play important roles in the temporal stages of replication. Here, we defined the impact on replication kinetics of the proteasome inhibitor, bortezomib. We demonstrate that bortezomib significantly reduces levels of viral genomes and infectious virions produced from a population of cells. Inhibition reduced expression of viral proteins that are influenced by genome synthesis. When added prior to 24 hpi, we observe decreases in PCNA and Cdk1 while increases in p21 whose regulations contribute to efficient replication. This response synergized with an antiviral, maribavir. Since some replication occurred, we tested the hypothesis that a subset of infected cells might break through inhibition. Initially, we simulated bortezomib activities using a mechanistic computational model of late-lytic replication. Upon reducing multiplicity of infection (MOI) <i>in silico</i>, we observed near-identical simulated results compared to experimental data. Next, we analyzed replication using live-cell imaging. This revealed treated cultures do contain a population of cells with fully developed late-stage cytoplasmic assembly compartments but at significantly lower numbers. We refer to this as the effective MOI. Overall, our studies support a hypothesis in which 20S proteasome inhibition disrupts HCMV replication by reducing the MOI to an effective MOI, defined by a fraction of infected cells capable of progressing to fulminant infection.IMPORTANCEHuman cytomegalovirus (HCMV) infection and reactivation continues to contribute to morbidity and mortality around the world. Antiviral compounds are available but have limitations. Here, we have defined the impact of the proteasome inhibitor bortezomib on HCMV replication. Proteasomal activities play a critical role in temporal changes required for replication. We demonstrate that disrupting these activities inhibits viral replication while likely supporting increased antiviral activity of the anti-HCMV agent, maribavir. Using a combination of live-cell imaging and computational tools, we discover that a subset of infected cells progresses to fulminant infection, which we define as the effective multiplicity of infection, and this subset would otherwise be missed when analyzing the average of the population.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0175124"},"PeriodicalIF":4.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801475","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":"Biographical Feature: In memoriam Jay A. Nelson (1948-2024).","authors":"Meaghan H Hancock","doi":"10.1128/jvi.01930-24","DOIUrl":"https://doi.org/10.1128/jvi.01930-24","url":null,"abstract":"","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0193024"},"PeriodicalIF":4.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801461","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":"Deubiquitinase USP37 enhances the anti-HIV-2/SIV ability of the host restriction factor SAMHD1.","authors":"Wenzhe Cui, Hongfei Wang, Yuan Gao, Xue Zhang, Jingguo Xin, Zhaolong Li, Guangquan Li, Wenying Gao, Wenyan Zhang","doi":"10.1128/jvi.01858-24","DOIUrl":"https://doi.org/10.1128/jvi.01858-24","url":null,"abstract":"<p><p>The Vpx protein encoded by HIV-2/simian immunodeficiency virus (SIV) can antagonize the restriction of the host intrinsic restriction factor, SAMHD1, in nondividing cells by promoting its polyubiquitination and subsequent degradation, thereby facilitating viral replication and immune evasion. However, the role of deubiquitinating enzymes (DUBs) in the dynamics of virus and host remains poorly understood. Here, we demonstrate that DUB USP37 significantly reverses the Vpx-mediated degradation of SAMHD1 in various HIV-2/SIV subtypes by interacting with SAMHD1 and removing its ubiquitin chains. Notably, USP37 deubiquitinates SAMHD1 by directly recognizing SAMHD1 rather than by targeting the E3 ubiquitin ligase. The deubiquitinase activity of USP37 and its ubiquitin interacting motifs are essential for the deubiquitination of SAMHD1, whereas the phosphorylation state of USP37 does not influence its activity. Additionally, USP37 enhances the suppression of the retrotransposition of LINE-1 elements by SAMHD1 via stabilizing SAMHD1. Our findings provide important evidence that enhancing the deubiquitinating activity of some DUBs results in the stability of the host restriction factor and might be a viable strategy against HIV/SIV infections.IMPORTANCESAMHD1 is a multifunctional protein, including restricting virus replication, maintaining genomic integrity through DNA repair, modulating the immune response by influencing the production of type I interferons and other cytokines, and affecting cancer cell proliferation and sensitivity to chemotherapy. However, HIV-2/simian immunodeficiency virus (SIV)-encoded Vpx and the host E3 ligase TRIM21 can induce the degradation of SAMHD1 via the ubiquitin-proteasome pathway. Therefore, it is necessary to find the strategy to stabilize SAMHD1. Our study demonstrates that the deubiquitinase USP37 reverses Vpx- and TRIM21-mediated degradation of SAMHD1, thereby inhibiting SIV replication and LINE-1 activity by stabilizing SAMHD1. Thus, we report a novel role of USP37, which represents a potentially useful target for the development of new drugs.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0185824"},"PeriodicalIF":4.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801463","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":"Third intracellular loop of HCMV US28 is necessary for signaling and viral reactivation.","authors":"Samuel Medica, Michael Denton, Nicole L Diggins, Olivia Kramer-Hansen, Lindsey B Crawford, Adam T Mayo, Wilma D Perez, Michael A Daily, Christopher J Parkins, Luke E Slind, Lydia J Pung, Whitney C Weber, Hannah K Jaeger, Zachary J Streblow, Gauthami Sulgey, Craig N Kreklywich, Timothy Alexander, Mette M Rosenkilde, Patrizia Caposio, Meaghan H Hancock, Daniel N Streblow","doi":"10.1128/jvi.01801-24","DOIUrl":"https://doi.org/10.1128/jvi.01801-24","url":null,"abstract":"<p><p>The human cytomegalovirus (HCMV) encoded chemokine receptor US28 plays a critical role in viral pathogenesis, mediating several processes such as cellular migration, differentiation, transformation, and viral latency and reactivation. Despite significant research examining the signal transduction pathways utilized by US28, the precise mechanism by which US28 activates these pathways remains unclear. We performed a mutational analysis of US28 to identify signaling domains that are critical for functional activities. Our results indicate that specific residues within the third intracellular loop (ICL3) of US28 are major determinants of G-protein coupling and downstream signaling activity. Alanine substitutions at positions S218, K223, and R225 attenuated US28-mediated activation of MAPK and RhoA signal transduction pathways. Furthermore, we show that mutations at positions S218, K223, or R225 result in impaired coupling to multiple Gα isoforms. However, these substitutions did not affect US28 plasma membrane localization or the receptor internalization rate. Utilizing CD34⁺ HPC models, we demonstrate that attenuation of US28 signaling <i>via</i> mutation of residues within the ICL3 region results in an inability of the virus to efficiently reactivate from latency. These results were recapitulated <i>in vivo</i>, utilizing a humanized mouse model of HCMV infection. Together, our results provide new insights into the mechanism by which US28 manipulates host signaling networks to mediate viral latency and reactivation. The results reported here will guide the development of targeted therapies to prevent HCMV-associated disease.IMPORTANCEHuman cytomegalovirus (HCMV) is a β-herpesvirus that infects between 44% and 100% of the world population. Primary infection is typically asymptomatic and results in the establishment of latent infection within CD34⁺hematopoietic progenitor cells (HPCs). However, reactivation from latent infection remains a significant cause of morbidity and mortality in immunocompromised individuals. The viral chemokine receptor US28 influences various cellular processes crucial for viral latency and reactivation, yet the precise mechanism by which US28 functions remains unclear. Through mutational analysis, we identified key residues within the third intracellular loop (ICL3) of US28 that govern G-protein coupling, downstream signaling, and viral reactivation <i>in vitro</i> and <i>in vivo</i>. These findings offer novel insights into how US28 manipulates host signaling networks to regulate HCMV latency and reactivation and expand our understanding of HCMV pathogenesis.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0180124"},"PeriodicalIF":4.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801480","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":"Erratum for Barbosa Bomfim et al., \"CGRP inhibits SARS-CoV-2 infection of bronchial epithelial cells, and its pulmonary levels correlate with viral clearance in critical COVID-19 patients\".","authors":"Caio César Barbosa Bomfim, Hugo Génin, Andréa Cottoignies-Callamarte, Sarah Gallois-Montbrun, Emilie Murigneux, Anette Sams, Arielle R Rosenberg, Sandrine Belouzard, Jean Dubuisson, Olivier Kosmider, Frédéric Pène, Benjamin Terrier, Morgane Bomsel, Yonatan Ganor","doi":"10.1128/jvi.02006-24","DOIUrl":"https://doi.org/10.1128/jvi.02006-24","url":null,"abstract":"","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0200624"},"PeriodicalIF":4.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801468","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":"Novel polymycoviruses are encapsidated in filamentous virions.","authors":"Zhenhao Han, Jingjing Jiang, Wenxing Xu","doi":"10.1128/jvi.01515-24","DOIUrl":"https://doi.org/10.1128/jvi.01515-24","url":null,"abstract":"&lt;p&gt;&lt;p&gt;&lt;i&gt;Polymycoviridae&lt;/i&gt; is a relatively new viral family that was established nearly 5 years ago, but their viral morphologies (naked or encapsidated) remain controversial since only one member namely, &lt;i&gt;Colletotrichum camelliae&lt;/i&gt; filamentous virus 1 (CcFV1), was identified as being encapsidated in filamentous virions. Here, three novel double-stranded RNA (dsRNA) viruses belonging to the family &lt;i&gt;Polymycoviridae&lt;/i&gt; were identified in three phytopathogenic fungal strains and tentatively named &lt;i&gt;Pseudopestalotiopsis camelliae&lt;/i&gt;-sinensis polymycovirus 1 (PcsPmV1), and &lt;i&gt;Phyllosticta capitalensis&lt;/i&gt; polymycovirus 1 and 2 (PhcPmV1 and 2), respectively. PcsPmV1 and PhcPmVs have five or six genomic dsRNAs, ranging from 1,055 to 2,405 bp, encoding five or seven putative open reading frames (ORFs), of which ORF1 encodes an RNA-dependent RNA polymerase, ORF5 encodes a prolein-alanine-serine-rich (P-A-S-rich) protein behaving as coat protein (CP); and dsRNAs 4 and 6 encode putative proteins with unknown functions and share no detectable identities with known viral sequences. Upon examination under transmission electron microscopy after purification from fungal mycelia, PcsPmV1 and PhcPmVs were found to be encapsidated in filamentous particles, as was a known polymycovirus, &lt;i&gt;Botryosphaeria dothidea&lt;/i&gt; RNA virus 1 (BdRV1), which was previously assumed to likely have no conventional virions. The morphology of PcsPmV1 was further supported by the observation that its particles could be decorated by polyclonal antibodies against its CP and bound by immuno-gold particles conjugated to the specific CP antibody. Together with CcFV1, BdRV1, PcsPmV1, and PhcPmVs, these provide strong evidence to support the notion that polymycoviruses are encapsidated in filamentous virions constituted by P-A-S-rich CPs. Moreover, their biological effects on their fungal hosts were assessed, suggesting that PcsPmV1 infection could enhance growth and virulence.IMPORTANCE&lt;i&gt;Polymycoviridae&lt;/i&gt;, a recently established viral family, has raised questions about encapsidation. Here, we identify and characterize three novel polymycoviral double-stranded RNA (dsRNA) viruses in phytopathogenic fungal strains, tentatively named &lt;i&gt;Pseudopestalotiopsis camelliae&lt;/i&gt;-sinensis polymycovirus 1, and &lt;i&gt;Phyllosticta capitalensis&lt;/i&gt; polymycovirus 1 and 2, respectively. These polymycoviruses possess five or six genomic dsRNAs, ranging from 1,055 to 2,405 bp, with two encoding putative proteins of unknown functions and sharing no detectable identities with known viral sequences. Their morphologies indicate filamentous virions constituted by proline-alanine-serine-rich coat proteins, observed using immunosorbent electron microscopy combined with immune-gold labeling techniques. Additionally, &lt;i&gt;Botryosphaeria dothidea&lt;/i&gt; RNA virus 1, previously assumed to lack conventional virions, is also shown to be encapsidated in filamentous particles. This study provides new evidence supporting ","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0151524"},"PeriodicalIF":4.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801472","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":"Enteroviral 3C protease cleaves N4BP1 to impair the host inflammatory response.","authors":"Dongjie Zhang, Yifan Xie, Jie Cao, Lisu Huang, Wenchun Fan","doi":"10.1128/jvi.01758-24","DOIUrl":"https://doi.org/10.1128/jvi.01758-24","url":null,"abstract":"<p><p>Enteroviral 3C protease (3Cpro) is an essential enzyme for viral replication and is responsible for combating the host anti-viral immune response by targeting cellular proteins for cleavage. The identification and characterization of 3Cpro substrates will contribute to our understanding of viral pathogenesis. In this study, we performed a motif search for 3Cpro substrates in the human protein database using FIMO, which refers to a common cleavage sequence of 3Cpro. We identified and characterized NEDD4-binding protein 1 (N4BP1), a key negative regulator of the NF-κB pathway, as a novel 3Cpro substrate. N4BP1 is cleaved at residue Q816 by 3Cpro from several human enteroviruses, resulting in the loss of its ability to regulate tumor necrosis factor alpha-activated NF-κB signaling. In addition, we found that mouse N4BP1, which has a threonine at the P1' site, is resistant to human enteroviral 3Cpro cleavage. However, rodent enteroviral 3Cpro derived from encephalomyocarditis virus (EMCV) can cleave both human and mouse N4BP1 at a species-specific site. By combining bioinformatic, biochemical, and cell biological approaches, we identified and characterized N4BP1 as a novel substrate of enteroviral 3Cpro. These findings provide valuable insights into the interplay between 3Cpro, its substrates, and viral pathogenesis.</p><p><strong>Importance: </strong>Targeting cellular proteins for cleavage by enteroviral 3Cpro is a conserved strategy used by enteroviruses to promote viral replication. While the cleavage of certain host proteins by 3Cpro may not affect viral replication, it is strongly associated with the pathogenesis of viral infection. In this study, we identified and characterized N4BP1, which plays such a role, using a combination of bioinformatic, biochemical, and cell biological approaches. Our data show that multiple 3Cpros cleave N4BP1 at residue Q816 and that cleavage of endogenous N4BP1 can occur during viral infection. N4BP1 has no effect on coxsackievirus B3 replication, but 3Cpro-induced N4BP1 cleavage abolishes its regulatory function in NF-κB signaling. We also show that mouse N4bp1 resists human enteroviral 3Cpro cleavage. In contrast, rodent enteroviral EMCV 3Cpro can target human and mouse N4BP1 for cleavage at different residues, which indicates that future investigations are needed to elucidate the potential mechanisms involved.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0175824"},"PeriodicalIF":4.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801465","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":"The segmented flavivirus Alongshan virus reduces mitochondrial mass by degrading STAT2 to suppress the innate immune response.","authors":"Yinghua Zhao, Liyan Sui, Mingming Pan, Fangyu Jin, Yuan Huang, Shu Fang, Mengmeng Wang, Lihe Che, Wenbo Xu, Nan Liu, Haicheng Gao, Zhijun Hou, Fang Du, Zhengkai Wei, Lesley Bell-Sakyi, Jixue Zhao, Kaiyu Zhang, Yicheng Zhao, Quan Liu","doi":"10.1128/jvi.01301-24","DOIUrl":"https://doi.org/10.1128/jvi.01301-24","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Alongshan virus (ALSV) is a newly discovered pathogen in the &lt;i&gt;Flaviviridae&lt;/i&gt; family, characterized by a unique multi-segmented genome that is distantly related to the canonical flaviviruses. Understanding the pathogenic mechanism of this emerging segmented flavivirus is crucial for the development of effective intervention strategies. In this study, we demonstrate that ALSV can infect various mammalian cells and induce the expression of antiviral genes. Furthermore, ALSV is sensitive to IFN-β, but it has developed strategies to counteract the host's type I IFN response. Mechanistically, ALSV's nonstructural protein NSP1 interacts with and degrades human STAT2 through an autophagy pathway, with species-dependent effects. This degradation directly inhibits the expression of interferon-stimulated genes (ISGs). Additionally, NSP1-mediated degradation of STAT2 disrupts mitochondrial dynamics, leading to mitophagy and inhibition of mitochondrial biogenesis. This, in turn, suppresses the host's innate immune response. Interestingly, we found that inhibiting mitophagy using 3-methyladenine and enhancing mitochondrial biogenesis with the PPARγ agonist pioglitazone can reverse NSP1-mediated inhibition of ISGs, suggesting that promoting mitochondrial mass could serve as an effective antiviral strategy. Specifically, the NSP1 methyltransferase domain binds to the key sites of F175/R176 located in the coiled-coil domain of STAT2. Our findings provide valuable insights into the intricate regulatory cross talk between ALSV and the host's innate immune response, shedding light on the pathogenesis of this emerging segmented flavivirus and offering potential intervention strategies.IMPORTANCEAlongshan virus (ALSV), a segmented flavivirus belonging to the &lt;i&gt;Flaviviridae&lt;/i&gt; family, was first identified in individuals who had been bitten by ticks in Northeastern China. ALSV infection is responsible for causing Alongshan fever, a condition characterized by various clinical symptoms, including fever, headache, skin rash, myalgia, arthralgia, depression, and coma. There is an urgent need for effective antiviral therapies. Here, we demonstrate that ALSV is susceptible to IFN-β but has developed mechanisms to counteract the host's innate immune response. Specifically, the ALSV nonstructural protein NSP1 interacts with STAT2, leading to its degradation via an autophagy pathway that exhibits species-dependent effects. Additionally, NSP1 disrupts mitochondrial dynamics and suppresses mitochondrial biogenesis, resulting in a reduction in mitochondrial mass, which ultimately contributes to the inhibition of the host's innate immune response. Interestingly, we found that inhibiting mitophagy and promoting mitochondrial biogenesis can reverse NSP1-mediated suppression of innate immune response by increasing mitochondrial mass. These findings provide valuable insights into the molecular mechanisms of ALSV pathogenesis and suggest potential therapeutic targets against ","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0130124"},"PeriodicalIF":4.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801478","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":"The neonatal Fc receptor (FcRn) is required for porcine reproductive and respiratory syndrome virus uncoating.","authors":"Kang Yang, Jiarui Dong, Jian Li, Rui Zhou, Xiangchao Jia, Zhijian Sun, Weida Zhang, Zili Li","doi":"10.1128/jvi.01218-24","DOIUrl":"https://doi.org/10.1128/jvi.01218-24","url":null,"abstract":"<p><p>Porcine reproductive and respiratory syndrome virus (PRRSV) continues to cause substantial economic losses to the pig industry worldwide. Previous studies from other groups showed that CD163 is required for PRRSV uncoating and genome release. However, CD163 does not interact with nucleocapsid (N) protein. In this study, the neonatal Fc receptor (FcRn) was demonstrated to be irreplaceable for PRRSV infection by knockdown, overexpression, antibodies or IgG blocking, knockout, and replenishment assays. FcRn was further revealed to be involved in PRRSV uncoating for the first time rather than viral attachment and internalization. In detail, FcRn was determined to colocalize with CD163 and PRRSV virions in early endosomes and specially interact with N protein in early endosomes. Taken together, these results provide evidence that FcRn is an essential cellular factor for PRRSV uncoating, which will be a promising target to interfere with the viral infection.IMPORTANCEPRRSV infection results in a severe swine disease affecting pig farming in the world. Although CD163 has been implicated as the uncoating receptor for PRRSV but the uncoating mechanism of PRRSV remains unclear. Here, we identified that FcRn facilitated virion uncoating <i>via</i> interaction with viral N protein in early endosomes. Our work actually expands the knowledge of PRRSV infection and provides an attractive therapeutic target for the prevention and control of PRRS.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0121824"},"PeriodicalIF":4.0,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801477","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":"The gE/gI complex is necessary for kinesin-1 recruitment during alphaherpesvirus egress from neurons.","authors":"Drishya Diwaker, DongHo Kim, Dylann Cordova-Martinez, Nivedita Pujari, Bryen A Jordan, Gregory A Smith, Duncan W Wilson","doi":"10.1128/jvi.01650-24","DOIUrl":"https://doi.org/10.1128/jvi.01650-24","url":null,"abstract":"<p><p>Following reactivation of a latent alphaherpesvirus infection, viral particles are assembled in neuronal cell bodies, trafficked anterogradely within axons to nerve termini, and spread to adjacent epithelial cells. The virally encoded membrane proteins US9p and the glycoprotein heterodimer gE/gI of pseudorabies virus (PRV) and herpes simplex virus type 1 (HSV-1) play critical roles in anterograde spread, likely as a tripartite gE/gI-US9p complex. Two kinesin motors, kinesin-1 and kinesin-3, are implicated in the egress of these viruses, but how gE/gI-US9p coordinates their activities is poorly understood. Here, we report that PRV, in addition to associating with the kinesin-3 motor KIF1A, recruits the neuronal kinesin-1 isoforms KIF5A and KIF5C, but not the broadly expressed isoform KIF5B, during egress from differentiated CAD neurons. Similarly, in the axons of dorsal root ganglia (DRG)-derived sensory neurons, PRV colocalized with KIF5C but not KIF5B. In differentiated CAD cells, the association of KIF1A with egressing PRV was dependent upon US9p, whereas the recruitment of KIF5 isoforms required gE/gI. Consistent with these findings, the number of PRV particles trafficking within CAD neurites and the axons of DRG neurons increased when kinesin-1 motor activity was upregulated by hyperacetylating microtubules using trichostatin A (TSA) or tubacin, and this enhanced trafficking depended upon the presence of gE/gI. We propose that, following its recruitment by US9p, KIF1A delivers PRV particles to a location where KIF5 motors are subsequently added by a gE/gI-dependent mechanism. KIF5A/C isoforms then serve to traffic viral particles along axons, resulting in characteristic recrudescent infection.</p><p><strong>Importance: </strong>Alphaherpesviruses include important human and veterinary pathogens that share a unique propensity to establish life-long latent infections in the peripheral nervous system. Upon reactivation, these viruses navigate back to body surfaces and transmit to new hosts. In this study, we demonstrate that the virus gE/gI-US9p membrane complex routes virus particles down this complex neuronal egress pathway by coordinating their association with multiple kinesin microtubule motors.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0165024"},"PeriodicalIF":4.0,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801476","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}