mBioPub Date : 2025-04-09Epub Date: 2025-03-12DOI: 10.1128/mbio.04067-24
Tingting Guo, Daniel H Haft, Daniel Wall
{"title":"Myxosortase: an intramembrane protease that sorts MYXO-CTERM proteins to the cell surface.","authors":"Tingting Guo, Daniel H Haft, Daniel Wall","doi":"10.1128/mbio.04067-24","DOIUrl":"10.1128/mbio.04067-24","url":null,"abstract":"<p><p>Cell surface proteins determine how cells interact with their biotic and abiotic environments. In social myxobacteria, a C-terminal protein sorting tag called MYXO-CTERM is universally found within the Myxococcota phylum, where their genomes typically contain dozens of proteins with this motif. MYXO-CTERM harbors a tripartite architecture: a short signature motif containing an invariant cysteine, followed by a transmembrane helix and a short arginine-rich C-terminal region localized in the cytoplasm. In <i>Myxococcus xanthus</i>, MYXO-CTERM is predicted to be posttranslationally lipidated and cleaved for subsequent cell surface localization by the type II secretion system. Here, following our bioinformatic discovery, we experimentally show that myxosortase (MrtX, MXAN_2755) is responsible for the C-terminal cleavage and cell surface anchoring of TraA, a prototypic cell surface receptor. The cleavage by MrtX depends on conserved cysteines within the MYXO-CTERM motif of TraA. <i>M. xanthus</i> mutants lacking myxosortase are defective in TraA-mediated outer membrane exchange and exhibit cell envelope defects. In a heterologous <i>Escherichia coli</i> expression system, the MYXO-CTERM motif is cleaved when MrtX is co-expressed. Therefore, MrtX represents a new family of sorting enzyme that enables cell surface localization of MYXO-CTERM proteins.IMPORTANCEThe CPBP (CaaX protease and bacteriocin processing) protease family is widespread across the three domains of life. Despite considerable research on eukaryotic homologs, prokaryotic CPBP family members remain largely unexplored. In this study, we experimentally reveal the function of a novel CPBP protease called myxosortase. Our findings show that myxosortase is responsible for the C-terminal cleavage and cell surface anchoring of substrate proteins containing MYXO-CTERM motifs in <i>Myxococcus xanthus</i>. MYXO-CTERM cleavage also occurred in a heterologous <i>Escherichia coli</i> host when myxosortase is co-expressed. This is the first report that a CPBP protease is involved in protein sorting in prokaryotes. This work provides important insights into the biogenesis and anchoring of cell surface proteins in gram-negative bacteria.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0406724"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
mBioPub Date : 2025-04-09Epub Date: 2025-03-20DOI: 10.1128/mbio.03809-24
Yining Deng, Santiago Navarro-Forero, Zhilong Yang
{"title":"Temporal expression classes and functions of vaccinia virus and mpox (monkeypox) virus genes.","authors":"Yining Deng, Santiago Navarro-Forero, Zhilong Yang","doi":"10.1128/mbio.03809-24","DOIUrl":"10.1128/mbio.03809-24","url":null,"abstract":"<p><p>Poxviruses comprise pathogens that are highly pathogenic to humans and animals, causing diseases such as smallpox and mpox (formerly monkeypox). The family also contains members developed as vaccine vectors and oncolytic agents to fight other diseases. Vaccinia virus is the prototype poxvirus and the vaccine used to eradicate smallpox. Poxvirus genes follow a cascade temporal expression pattern, categorized into early, intermediate, and late stages using distinct transcription factors. This review comprehensively summarized the temporal expression classification of over 200 vaccinia virus genes. The relationships between expression classes and functions, as well as different branches of immune responses, were discussed. Based on the vaccinia virus orthologs, we classified the temporal expression classes of all the mpox virus genes, including a few that were not previously annotated with orthologs in vaccinia viruses. Additionally, we reviewed the functions of all vaccinia virus genes based on the up-to-date published papers. This review provides a readily usable resource for researchers working on poxvirus biology, medical countermeasures, and poxvirus utility development.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0380924"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
mBioPub Date : 2025-04-09Epub Date: 2025-03-06DOI: 10.1128/mbio.02472-24
Dukwon Lee, Yeongjin Baek, Migak Park, Doyeon Kim, Kyumi Byun, Jaekyung Hyun, Nam-Chul Ha
{"title":"3D meshwork architecture of the outer coat protein CotE: implications for bacterial endospore sporulation and germination.","authors":"Dukwon Lee, Yeongjin Baek, Migak Park, Doyeon Kim, Kyumi Byun, Jaekyung Hyun, Nam-Chul Ha","doi":"10.1128/mbio.02472-24","DOIUrl":"10.1128/mbio.02472-24","url":null,"abstract":"<p><p><i>Bacillus cereus,</i> a Gram-positive aerobic bacterium commonly found in soil, food, and water, forms endospores that can withstand harsh environmental conditions. The endospores are encased in a protective spore coat consisting of multiple layers of proteins, among which, CotE serves as a crucial morphogenetic protein within the outer coat. In this study, we observed that the homotrimeric CotE protein underwent further oligomerization induced by Ca<sup>2+</sup> and was subsequently dissociated by dipicolinic acid, a compound released from the spore core during germination. Through cryo-electron microscopy and tomography analyses of the Ca<sup>2+</sup>-induced CotE oligomer, combined with structural predictions and biochemical studies, we propose a three-dimensional meshwork organization facilitated by tryptophan-based interactions between CotE trimers. The resulting meshwork was organized in a defective diamond-like tetrahedral configuration. These insights enhance our understanding of how CotE contributes to endospore morphogenesis and germination through the rapid disassembly of these layers.</p><p><strong>Importance: </strong>Bacterial endospores are highly resilient structures that allow bacteria to survive extreme environmental conditions, making them a significant concern in food safety and healthcare. The protein CotE plays a critical role in forming the protective outer coat of these endospores. Our research uncovers the three-dimensional meshwork architecture of CotE and reveals how it contributes to the structural integrity and rapid disassembly of endospores during germination. By understanding CotE's unique 3D structure and its interaction with other molecules, we gain valuable insights into how bacterial endospores are formed and how they can be effectively targeted for sterilization. This work not only advances our fundamental knowledge of bacterial endospore biology but also has potential applications in developing new strategies to combat bacterial contamination and improve sterilization techniques in the food and healthcare industries.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0247224"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
mBioPub Date : 2025-04-09Epub Date: 2025-02-27DOI: 10.1128/mbio.00648-25
Ira Blader, Felicia Goodrum, Michael J Imperiale, Arturo Casadevall, Cesar A Arias, Andreas Baumler, Carey-Ann D Burnham, Christina A Cuomo, Corrella S Detweiler, Graeme N Forrest, Jack A Gilbert, Susan Lovett, Stanley Maloy, Alexander McAdam, Irene Newton, Gemma Reguera, George A O'Toole, Patrick D Schloss, Ashley Shade, Marvin Whiteley
{"title":"A call for the United States to continue investing in science.","authors":"Ira Blader, Felicia Goodrum, Michael J Imperiale, Arturo Casadevall, Cesar A Arias, Andreas Baumler, Carey-Ann D Burnham, Christina A Cuomo, Corrella S Detweiler, Graeme N Forrest, Jack A Gilbert, Susan Lovett, Stanley Maloy, Alexander McAdam, Irene Newton, Gemma Reguera, George A O'Toole, Patrick D Schloss, Ashley Shade, Marvin Whiteley","doi":"10.1128/mbio.00648-25","DOIUrl":"10.1128/mbio.00648-25","url":null,"abstract":"","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0064825"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
mBioPub Date : 2025-04-09Epub Date: 2025-03-04DOI: 10.1128/mbio.00278-25
Kevin E Ramos, Nisreen M A Okba, Jessica Tan, Pooja Bandawane, Philip Meade, Madhumathi Loganathan, Benjamin Francis, Sergey Shulenin, Frederick W Holtsberg, M Javad Aman, Meagan McMahon, Florian Krammer, Jonathan R Lai
{"title":"Correction for Ramos et al., \"Broadly protective bispecific antibodies that simultaneously target influenza virus hemagglutinin and neuraminidase\".","authors":"Kevin E Ramos, Nisreen M A Okba, Jessica Tan, Pooja Bandawane, Philip Meade, Madhumathi Loganathan, Benjamin Francis, Sergey Shulenin, Frederick W Holtsberg, M Javad Aman, Meagan McMahon, Florian Krammer, Jonathan R Lai","doi":"10.1128/mbio.00278-25","DOIUrl":"10.1128/mbio.00278-25","url":null,"abstract":"","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0027825"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143541305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
mBioPub Date : 2025-04-09Epub Date: 2025-03-05DOI: 10.1128/mbio.00216-25
Sofiya Kandelis-Shalev, Manish Goyal, Tal Elam, Shany Assaraf, Noa Dahan, Omer Farchi, Eduard Berenshtein, Ron Dzikowski
{"title":"SUN-domain proteins of the malaria parasite <i>Plasmodium falciparum</i> are essential for proper nuclear division and DNA repair.","authors":"Sofiya Kandelis-Shalev, Manish Goyal, Tal Elam, Shany Assaraf, Noa Dahan, Omer Farchi, Eduard Berenshtein, Ron Dzikowski","doi":"10.1128/mbio.00216-25","DOIUrl":"10.1128/mbio.00216-25","url":null,"abstract":"<p><p>The protozoan parasite <i>Plasmodium falciparum</i>, which is responsible for the deadliest form of human malaria, accounts for over half a million deaths a year. These parasites proliferate in human red blood cells by consecutive rounds of closed mitoses called schizogony. Their virulence is attributed to their ability to modify the infected red cells to adhere to the vascular endothelium and to evade immunity through antigenic switches. Spatial dynamics at the nuclear periphery were associated with the regulation of processes that enable the parasites to establish long-term infection. However, our knowledge of components of the nuclear envelope (NE) in <i>Plasmodium</i> remains limited. One of the major protein complexes at the NE is the linker of nucleoskeleton and cytoskeleton (LINC) complex that forms a connecting bridge between the cytoplasm and the nucleus through the interaction of SUN and KASH domain proteins. Here, we have identified two SUN-domain proteins as possible components of the LINC complex of <i>P. falciparum</i> and show that their proper expression is essential for the parasite's proliferation in human red blood cells, and their depletion leads to the formation of membranous whorls and morphological changes of the NE. In addition, their differential expression highlights different functions at the nuclear periphery as PfSUN2 is specifically associated with heterochromatin, while PfSUN1 expression is essential for activation of the DNA damage response. Our data provide indications for the involvement of the LINC complex in crucial biological processes in the intraerythrocytic development cycle of malaria parasites.</p><p><strong>Importance: </strong><i>Plasmodium falciparum</i>, the parasite causing the deadliest form of malaria, is able to thrive in its human host by tight regulation of cellular processes, orchestrating nuclear dynamics with cytoplasmic machineries that are separated by the nuclear envelope. One of the major protein complexes that connect nuclear and cytoplasmic processes in eukaryotes is the linker of nucleoskeleton and cytoskeleton (LINC) complex. However, while the nuclear periphery of <i>P. falciparum</i> was implicated in several important functions, the role of the LINC complex in Plasmodium biology is unknown. Here, we identify two components of <i>P. falciparum</i> LINC complex and demonstrate that they are essential for the parasites' proliferation in human blood, and their depletion leads to the formation of morphological changes in the cell. In addition, the two components have different functions in activating the DNA damage response and in their association with heterochromatin. Our data provide evidence for their essential roles in the parasites' cell cycle.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0021625"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
mBioPub Date : 2025-04-09Epub Date: 2025-03-20DOI: 10.1128/mbio.03728-24
Ching Wooen Sze, Michael J Lynch, Kai Zhang, David B Neau, Steven E Ealick, Brian R Crane, Chunhao Li
{"title":"Lactate dehydrogenase is the Achilles' heel of Lyme disease bacterium <i>Borreliella burgdorferi</i>.","authors":"Ching Wooen Sze, Michael J Lynch, Kai Zhang, David B Neau, Steven E Ealick, Brian R Crane, Chunhao Li","doi":"10.1128/mbio.03728-24","DOIUrl":"10.1128/mbio.03728-24","url":null,"abstract":"<p><p>As a zoonotic pathogen, the Lyme disease bacterium <i>Borreliella burgdorferi</i> has evolved unique metabolic pathways, some of which are specific and essential for its survival and thus present as ideal targets for developing new therapeutics. <i>B. burgdorferi</i> dispenses with the use of thiamin as a cofactor and relies on lactate dehydrogenase (BbLDH) to convert pyruvate to lactate for balancing NADH/NAD<sup>+</sup> ratios. This report first demonstrates that BbLDH is a canonical LDH with some unique biochemical and structural features. A loss-of-function study then reveals that BbLDH is essential for <i>B. burgdorferi</i> survival and infectivity, highlighting its therapeutic potential. Drug screening identifies four previously unknown LDH inhibitors with minimal cytotoxicity, two of which inhibit <i>B. burgdorferi</i> growth. This study provides mechanistic insights into the function of BbLDH in the pathophysiology of <i>B. burgdorferi</i> and lays the groundwork for developing genus-specific metabolic inhibitors against <i>B. burgdorferi</i> and potentially other tick-borne pathogens as well.</p><p><strong>Importance: </strong>Lyme disease (LD) is the most commonly reported tick-borne illness in the U.S. and Europe, and its geographic distribution is continuously expanding worldwide. Though early LD can be treated with antibiotics, chronic LD is recalcitrant to antibiotic treatments and thus requires multiple courses of antibiotic therapy. Currently, there are no human vaccines nor prophylactic antibiotics to prevent LD. As the causative agent of LD, <i>Borreliella burgdorferi</i> has evolved unique metabolic pathways, some of which are specific and essential for its survival and thus present as ideal targets for developing new therapeutics. By using an approach of genetics, biochemistry, structural biology, drug screening, and animal models, this report provides evidence that lactate dehydrogenase can be a potential target for developing genus-specific metabolic inhibitors against <i>B. burgdorferi</i> and potentially other tick-borne pathogens as well.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0372824"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
mBioPub Date : 2025-04-09Epub Date: 2025-03-12DOI: 10.1128/mbio.00595-25
Jovany J Betancourt, Minna Ding, J Marina Yoder, Issa Mutyaba, Hannah M Atkins, Gabriela De la Cruz, David B Meya, Kirsten Nielsen
{"title":"Erratum for Betancourt et al., \"Pulmonary granuloma formation during latent <i>Cryptococcus neoformans</i> infection in C3HeB/FeJ mice involves progression through three immunological phases\".","authors":"Jovany J Betancourt, Minna Ding, J Marina Yoder, Issa Mutyaba, Hannah M Atkins, Gabriela De la Cruz, David B Meya, Kirsten Nielsen","doi":"10.1128/mbio.00595-25","DOIUrl":"10.1128/mbio.00595-25","url":null,"abstract":"","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0059525"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
mBioPub Date : 2025-04-09Epub Date: 2025-02-25DOI: 10.1128/mbio.03588-24
Younghwan Kwak, Jacob A Argandona, Sen Miao, Thomas J Son, Allison K Hansen
{"title":"A dual insect symbiont and plant pathogen improves insect host fitness under arginine limitation.","authors":"Younghwan Kwak, Jacob A Argandona, Sen Miao, Thomas J Son, Allison K Hansen","doi":"10.1128/mbio.03588-24","DOIUrl":"10.1128/mbio.03588-24","url":null,"abstract":"<p><p>Some facultative bacterial symbionts are known to benefit insects, but nutritional advantages are rare among these non-obligate symbionts. Here, we demonstrate that the facultative symbiont <i>Candidatus Liberibacter psyllaurous</i> enhances the fitness of its psyllid insect host, <i>Bactericera cockerelli</i>, by providing nutritional benefits. <i>L. psyllaurous</i>, an unculturable pathogen of solanaceous crops, also establishes a close relationship with its insect vector, <i>B. cockerelli</i>, increasing in titer during insect development, vertically transmitting through eggs, and colonizing various tissues, including the bacteriome, which houses the obligate nutritional symbiont, <i>Carsonella. Carsonella</i> supplies essential amino acids to its insect host but has gaps in some of its essential amino acid pathways that the psyllid complements with its own genes, many of which have been acquired through horizontal gene transfer (HGT) from bacteria. Our findings reveal that <i>L. psyllaurous</i> increases psyllid fitness on plants by reducing developmental time and increasing adult weight. In addition, through metagenomic sequencing, we reveal that <i>L. psyllaurous</i> maintains complete pathways for synthesizing the essential amino acids arginine, lysine, and threonine, unlike the psyllid's other resident microbiota, <i>Carsonella,</i> and two co-occurring <i>Wolbachia</i> strains. RNA sequencing reveals the downregulation of a HGT collaborative psyllid gene (<i>ASL</i>), which indicates a reduced demand for arginine supplied by <i>Carsonella</i> when the psyllid is infected with <i>L. psyllaurous</i>. Notably, artificial diet assays show that <i>L. psyllaurous</i> enhances psyllid fitness on an arginine-deplete diet. These results corroborate the role of <i>L. psyllaurous</i> as a beneficial insect symbiont, contributing to the nutrition of its insect host.IMPORTANCEUnlike obligate symbionts that are permanently associated with their hosts, facultative symbionts rarely show direct nutritional contributions, especially under nutrient-limited conditions. This study demonstrates, for the first time, that <i>Candidatus Liberibacter psyllaurous</i>, a facultative symbiont and a plant pathogen, enhances the fitness of its <i>Bactericera cockerelli</i> host by supplying an essential nutrient arginine that is lacking in the plant sap diet. Our findings reveal how facultative symbionts can play a vital role in helping their insect hosts adapt to nutrient-limited environments. This work provides new insights into the dynamic interactions between insect hosts, their symbiotic microbes, and their shared ecological niches, broadening our understanding of symbiosis and its role in shaping adaptation and survival.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0358824"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
mBioPub Date : 2025-04-09Epub Date: 2025-02-25DOI: 10.1128/mbio.03395-24
Lei Wu, Ya Yan, Ye Yuan, Zhenchao Zhao, Weiyu Qu, Xiangyu Huang, Haiwei Wang, Pingwei Li, Xin Li
{"title":"Viral protease binds to nucleosomal DNA and cleaves nuclear cGAS that attenuates type I interferon.","authors":"Lei Wu, Ya Yan, Ye Yuan, Zhenchao Zhao, Weiyu Qu, Xiangyu Huang, Haiwei Wang, Pingwei Li, Xin Li","doi":"10.1128/mbio.03395-24","DOIUrl":"10.1128/mbio.03395-24","url":null,"abstract":"<p><p>Nuclear cyclic GMP-AMP synthetase (cGAS) binds to nucleosome with high affinity to prevent its activation by self-DNA. Upon stimulation with double-stranded DNA, cGAS is activated and translocates from the nucleus to the cytoplasm, guided by its N-terminal domain. However, it remains unclear whether viruses can hijack cGAS translocation and regulate its activation. Here, we discovered that the protease 3C of picornavirus Seneca Valley virus (SVV) translocates from the cytoplasm to the nucleus upon viral infection and binds to nuclear DNA. Protease 3C specifically cleaves histone H2A while leaving other histone proteins unaffected. Additionally, DNA binding enhances the protease 3C's ability to cleave nuclear cGAS, leading to its retention in the nucleus. This, in turn, suppresses the induction of type I interferon (IFN-I) following poly(dA:dT) stimulation. These findings reveal a novel mechanism by which a viral protease binds nuclear DNA, cleaves nuclear cGAS and histone H2A, and thereby mislocalizes cGAS, facilitating immune evasion.</p><p><strong>Importance: </strong>Cyclic GMP-AMP synthetase (cGAS) is robustly expressed in the nucleus and tightly tethered by chromatin to prevent its activation with self-DNA. During stimulation or infection, nuclear cGAS is activated and translocates from the nucleus to the cytoplasm. However, the viral strategies specifically targeting nuclear cGAS are completely unexplored. Here, we discovered that protease 3C of Seneca Valley virus translocates from the cytoplasm to the nucleus upon viral infection, binds to nuclear DNA, and specifically cleaves H2A. Furthermore, DNA binding to 3C enhances the cleavage of nuclear cGAS within its N-terminal domain. The hindrance of cGAS translocation from the nucleus to the cytoplasm results in the suppression of IFN-I induction and leads to immune evasion. This work uncovers a unique mechanism wherein a viral protease binds to nuclear DNA and cleaves nuclear cGAS and histone H2A, leading to viral evasion of cGAS-mediated immune restriction.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0339524"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}