mBio最新文献

{"title":"Mono-allelic epigenetic regulation of polycistronic transcription initiation by RNA polymerase II in <i>Trypanosoma brucei</i>.","authors":"Rudo Kieft, Laura Cliffe, Haidong Yan, Robert J Schmitz, Stephen L Hajduk, Robert Sabatini","doi":"10.1128/mbio.02328-24","DOIUrl":"10.1128/mbio.02328-24","url":null,"abstract":"<p><p>Unique for a eukaryote, protein-coding genes in trypanosomes are arranged in polycistronic transcription units (PTUs). This genome arrangement has led to a model where Pol II transcription of PTUs is unregulated and changes in gene expression are entirely post-transcriptional. <i>Trypanosoma brucei brucei</i> is unable to infect humans because of its susceptibility to an innate immune complex, trypanosome lytic factor (TLF) in the circulation of humans. The initial step in TLF-mediated lysis of <i>T.b.brucei</i> requires high affinity haptoglobin/hemoglobin receptor (HpHbR) binding. Here, we demonstrate that by <i>in vitro</i> selection with TLF, resistance is obtained in a stepwise process correlating with loss of HpHbR expression at an allelic level. RNA-seq, Pol II ChIP, and run-on analysis indicate HpHbR silencing is at the transcriptional level, where loss of Pol II binding at the promoter region specifically shuts down transcription of the HpHbR-containing gene cluster and the adjacent opposing gene cluster. Reversible transcriptional silencing of the divergent PTUs correlates with DNA base J modification of the shared promoter region. Base J function in establishing transcriptional silencing, rather than maintenance, is suggested by the maintenance of PTU silencing following the inhibition of J-biosynthesis and subsequent loss of the modified DNA base. Therefore, we show that epigenetic mechanisms exist to regulate gene expression via Pol II transcription initiation of gene clusters in a mono-allelic fashion. These findings suggest epigenetic chromatin-based regulation of gene expression is deeply conserved among eukaryotes, including early divergent eukaryotes that rely on polycistronic transcription.IMPORTANCEThe single-cell parasite <i>Trypanosoma brucei</i> causes lethal diseases in both humans and livestock. <i>T. brucei</i> undergoes multiple developmental changes to adapt in different environments during its digenetic life cycle. With protein-coding genes organized as polycistronic transcription and apparent absence of promoter-mediated regulation of transcription initiation, it is believed that developmental gene regulation in trypanosomes is essentially post-transcriptional. In this study, we found reversible Pol II transcriptional silencing of two adjacent polycistronic gene arrays that correlate with the novel DNA base J modification of the shared promoter region. Our findings support epigenetic regulation of Pol II transcription initiation as a viable mechanism of gene expression control in <i>T. brucei</i>. This has implications for our understanding how trypanosomes utilize polycistronic genome organization to regulate gene expression during its life cycle.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0232824"},"PeriodicalIF":5.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11796357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Pseudomonas aeruginosa</i> alkyl quinolone response is dampened by <i>Enterococcus faecalis</i>.","authors":"Maggie M Fink, Abigail A Weaver, Dharmeshkumar Parmar, Jon E Paczkowski, Lingyun Li, Maggie K Klaers, Ella A Junker, Elizabeth A Jarocki, Jonathan V Sweedler, Joshua D Shrout","doi":"10.1128/mbio.03320-24","DOIUrl":"10.1128/mbio.03320-24","url":null,"abstract":"<p><p>The bacterium <i>Pseudomonas aeruginosa</i> is an opportunistic pathogen that can cause lung, skin, wound, joint, urinary tract, and eye infections. While <i>P. aeruginosa</i> is known to exhibit a robust competitive response toward other bacterial species, this bacterium is frequently identified in polymicrobial infections where multiple species survive. For example, in prosthetic joint infections, <i>P. aeruginosa</i> can be identified along with other pathogenic bacteria including <i>Staphylococcus aureus</i>, <i>Enterococcus faecalis</i>, and <i>Corynebacterium striatum</i>. Here, we have explored the survival and behavior of such microbes and find that <i>E. faecalis</i> readily survives culturing with <i>P. aeruginosa</i> while other tested species do not. In each of the tested conditions, <i>E. faecalis</i> growth remained unchanged by the presence of <i>P. aeruginosa</i>, indicating a unique mutualistic interaction between the two species. We find that <i>E. faecalis</i> proximity leads <i>P. aeruginosa</i> to attenuate competitive behaviors as exemplified by reduced production of <i>Pseudomonas</i> quinolone signal and pyocyanin. Reduced alkyl quinolones are important to <i>E. faecalis</i> as these will grow in supernatant from a quinolone mutant but not <i>P. aeruginosa</i> wild-type in planktonic culture. The reduced pyocyanin production of <i>P. aeruginosa</i> is attributable to production of ornithine by <i>E. faecalis</i>, which we recapitulate by adding exogenous ornithine to <i>P. aeruginosa</i> monocultures. Similarly, co-culture with an ornithine-deficient strain of <i>E. faecalis</i> leads <i>P. aeruginosa</i> to yield near monoculture amounts of pyocyanin. Here, we directly demonstrate how notorious pathogens such as <i>P. aeruginosa</i> might persist in polymicrobial infections under the influence of metabolites produced by other bacterial species.</p><p><strong>Importance: </strong>While we now appreciate that many infections are polymicrobial, we understand little of the specific actions between a given set of microbes to enable combinatorial survival and pathogenesis. The bacteria <i>Pseudomonas aeruginosa</i> and <i>Enterococcus faecalis</i> are both prevalent pathogens in wound, urinary tract, and bacteremic infections. While <i>P. aeruginosa</i> often kills other species in standard laboratory culture conditions, we present here that <i>E. faecalis</i> can be reliably co-cultured with <i>P. aeruginosa</i>. We specifically detail that ornithine produced by <i>E. faecalis</i> reduces the <i>Pseudomonas</i> quinolone signal response of <i>P. aeruginosa</i>. This reduction of the <i>Pseudomonas</i> quinolone signal response aids <i>E. faecalis</i> growth.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0332024"},"PeriodicalIF":5.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11796420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142895976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HIV-1 transcription start sites usage and its impact on unspliced RNA functions in people living with HIV.","authors":"Saiful Islam, Frank Maldarelli, Olga A Nikolaitchik, Zetao Cheng, Robert Gorelick, Maria A Nikolaitchik, Vinay K Pathak, Wei-Shau Hu","doi":"10.1128/mbio.03576-24","DOIUrl":"10.1128/mbio.03576-24","url":null,"abstract":"<p><p>HIV-1 unspliced RNA serves two distinct functions during viral replication: it is packaged into particles as the viral genome, and it is translated to generate Gag/Gag-Pol polyproteins required for virus assembly. Recent studies have demonstrated that in cultured cells, HIV-1 uses multiple transcription start sites to generate several unspliced RNA species, including two major transcripts with three and one 5' guanosine, referred to as 3G and 1G RNA, respectively. Although nearly identical, 1G RNA is selected over 3G RNA to be packaged as the virion genome, indicating that these RNA species are functionally distinct. Currently, our understanding of HIV-1 transcription start site usage and the functions of RNA species is based on studies using cultured cells. Here, we examined samples from people living with HIV to investigate HIV-1 transcription start site usage and its impact on RNA function. Using paired samples collected from the same participants on the same date, we examined the HIV-1 unspliced RNA species in infected cells (PBMC) and in viruses (plasma). Our findings demonstrate that in people living with HIV, the virus uses multiple transcription start sites to generate several unspliced transcripts, including 3G and 1G RNA. Furthermore, we observed an enrichment of 1G RNA in the paired plasma samples, indicating a preferential packaging of 1G RNA <i>in vivo</i>. Our study illustrates the complex regulation of HIV-1 unspliced RNA in people living with HIV and provides valuable insights into how HIV-1 unspliced RNAs serve their functions <i>in vivo</i>.IMPORTANCEHIV-1 virions must contain unspliced RNA and its translation products to maintain infectivity. How HIV-1 unspliced RNA fulfills these two essential and yet distinct roles in viral replication has been a long-standing question in the field. In this report, we demonstrate that in people living with HIV, the virus uses multiple transcription start sites to generate several unspliced RNA species that are 99% identical in sequence but differ functionally. One of the RNA species, 1G RNA, is selected over other HIV-1 unspliced RNAs to be packaged into viral particles. These findings are consistent with previous cell-culture-based observations and provide insights into how HIV-1 regulates its unspliced RNA function in people living with HIV.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0357624"},"PeriodicalIF":5.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11796365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142895983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Influenza B virus infection alters the regenerative potential of murine alveolar type 2 pneumocytes.","authors":"Satoko Nakano, Cait E Hamele, Aleksandra Tata, Purushothama Rao Tata, Nicholas S Heaton","doi":"10.1128/mbio.02743-24","DOIUrl":"10.1128/mbio.02743-24","url":null,"abstract":"<p><p>Respiratory epithelial cells can survive direct infection by influenza viruses, and the long-term consequences of that infection have been characterized in a subset of proximal airway cell types. The impact on the cells that survive viral infection in the distal lung epithelia, however, is much less well-characterized. Utilizing a Cre-expressing influenza B virus (IBV) and a lox-stop-lox tdTomato reporter mouse model, we identified that alveolar type 2 (AT2) pneumocytes, a progenitor cell type in the distal lung, can survive viral infection. We show that survival of infection is associated with transcriptional dysregulation compared to bystander AT2 pneumocytes from the same lung. Furthermore, <i>ex vivo</i> experiments revealed a significant reduction in proliferation rates in survivor AT2 pneumocytes compared to matched, non-directly infected bystander cells. Our findings not only enhance our understanding of the AT2 pneumocyte response to IBV infection but could also have broader implications for the mechanisms of respiratory epithelial repair post-viral infection.</p><p><strong>Importance: </strong>Alveolar type 2 (AT2) pneumocytes are a cell type critical for repair of the distal lung after an injury, such as a viral infection. After epithelial damage, AT2 pneumocytes proliferate for both self-renewal and differentiation into type I pneumocytes to repopulate the epithelium. Theoretically, some of the long-term lung sequelae associated with viral infections could be the result of inappropriate AT2 behavior. Here, the authors report that during an influenza B virus infection, some of the actively infected AT2 pneumocytes can ultimately eliminate all traces of the viral RNA and persist in the host long term. As a consequence of having been infected, however, the cells display an altered transcriptional profile and decreased proliferative capacity. These data together suggest a mechanism for how an acute viral infection can have long-term impacts on the pulmonary system.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0274324"},"PeriodicalIF":5.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11796384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142914982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction for Choy et al., \"Ergosterol distribution controls surface structure formation and fungal pathogenicity\".","authors":"Hau Lam Choy, Elizabeth A Gaylord, Tamara L Doering","doi":"10.1128/mbio.03550-24","DOIUrl":"10.1128/mbio.03550-24","url":null,"abstract":"","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0355024"},"PeriodicalIF":5.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11796417/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142837242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"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.03610-24","DOIUrl":"10.1128/mbio.03610-24","url":null,"abstract":"<p><p><i>Cryptococcus neoformans</i> is a fungal pathogen that can cause lethal disease in immunocompromised patients. Immunocompetent host immune responses, such as formation of pulmonary granulomas, control the infection and prevent disseminated disease. Little is known about the immunological conditions establishing the latent infection granuloma in the lungs. To investigate this, we performed an analysis of pulmonary immune cell populations, cytokine changes, and granuloma formation during infection with a latent disease-causing clinical isolate in C3HeB/FeJ mice over 360 days. We found that latently infected mice progress through three phases of granuloma formation where different immune profiles dominate: an early phase characterized by eosinophilia, high IL-4/IL-13, and <i>C. neoformans</i> proliferation in the lungs; an intermediate phase characterized by multinucleated giant cell formation, high IL-1α/IFNγ, granuloma expansion, and increased blood antigen levels; and a late phase characterized by a significant expansion of T cells, granuloma condensation, and decreases in lung fungal burden and blood antigen levels. These findings highlight a complex series of immune changes that occur during the establishment of granulomas that control <i>C. neoformans</i> in the lungs and lay the foundation for studies to identify critical beneficial immune responses to <i>Cryptococcus</i> infections.IMPORTANCE<i>Cryptococcus neoformans</i> is a fungal pathogen that disseminates from the lungs to the brain to cause fatal disease. Latent C. <i>neoformans</i> infection in the lungs is controlled by organized collections of immune cells called granulomas. The formation and structure of <i>Cryptococcus</i> granulomas are poorly understood due to inconsistent human pathology results and disagreement between necrotic granuloma-forming rat models and non-necrotic granuloma-forming mouse models. To overcome this, we investigated granuloma formation during latent <i>C. neoformans</i> infection in the C3HeB/FeJ mouse strain which forms necrotic lung granulomas in response to other pathogens. We found that latent <i>C. neoformans</i> granuloma formation progresses through phases that we described as early, intermediate, and late with different immune response profiles and granulomatous characteristics. Ultimately, we show that C3HeB/FeJ mice latently infected with <i>C. neoformans</i> form non-necrotic granulomas and could provide a novel mouse model to investigate host immune response profiles.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0361024"},"PeriodicalIF":5.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11796415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Virulence factor discovery identifies associations between the Fic gene family and Fap2⁺ fusobacteria in colorectal cancer microbiomes.","authors":"Geicho Nakatsu, Duhyun Ko, Monia Michaud, Eric A Franzosa, Xochitl C Morgan, Curtis Huttenhower, Wendy S Garrett","doi":"10.1128/mbio.03732-24","DOIUrl":"10.1128/mbio.03732-24","url":null,"abstract":"<p><p><i>Fusobacterium</i> is a bacterium associated with colorectal cancer (CRC) tumorigenesis, progression, and metastasis. Fap2 is a fusobacteria-specific outer membrane galactose-binding lectin that mediates <i>Fusobacterium</i> adherence to and invasion of CRC tumors. Advances in omics analyses provide an opportunity to profile and identify microbial genomic features that correlate with the cancer-associated bacterial virulence factor Fap2. Here, we analyze genomes of <i>Fusobacterium</i> colon tumor isolates and find that a family of post-translational modification enzymes containing Fic domains is associated with Fap2 positivity in these strains. We demonstrate that Fic family genes expand with the presence of Fap2 in the fusobacterial pangenome. Through comparative genomic analysis, we find that Fap2⁺ Fusobacteriota are highly enriched with Fic gene families compared to other cancer-associated and human gut microbiome bacterial taxa. Using a global data set of CRC shotgun metagenomes, we show that fusobacterial Fic and Fap2 genes frequently co-occur in the fecal microbiomes of individuals with late-stage CRC. We further characterize specific Fic gene families harbored by Fap2⁺ <i>Fusobacterium animalis</i> genomes and detect recombination events and elements of horizontal gene transfer via synteny analysis of Fic gene loci. Exposure of a <i>F. animalis</i> strain to a colon adenocarcinoma cell line increases gene expression of fusobacterial Fic and virulence-associated adhesins. Finally, we demonstrate that Fic proteins are synthesized by <i>F. animalis</i> as Fic peptides are detectable in <i>F. animalis</i> monoculture supernatants. Taken together, our study uncovers Fic genes as potential virulence factors in Fap2⁺ fusobacterial genomes.IMPORTANCEAccumulating data support that bacterial members of the intra-tumoral microbiota critically influence colorectal cancer progression. Yet, relatively little is known about non-adhesin fusobacterial virulence factors that may influence carcinogenesis. Our genomic analysis and expression assays in fusobacteria identify Fic domain-containing genes, well-studied virulence factors in pathogenic bacteria, as potential fusobacterial virulence features. The Fic family proteins that we find are encoded by fusobacteria and expressed by <i>Fusobacterium animalis</i> merit future investigation to assess their roles in colorectal cancer development and progression.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0373224"},"PeriodicalIF":5.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11796403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142979016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping <i>C. difficile</i> TcdB interactions with host cell-surface and intracellular factors using proximity-dependent biotinylation labeling.","authors":"Jennifer S Ward, Karl J Schreiber, John Tam, Ji-Young Youn, Roman A Melnyk","doi":"10.1128/mbio.03336-24","DOIUrl":"10.1128/mbio.03336-24","url":null,"abstract":"<p><p>Many bacterial toxins exert their cytotoxic effects by enzymatically inactivating one or more cytosolic targets in host cells. To reach their intracellular targets, these toxins possess functional domains or subdomains that interact with and exploit various host factors and biological processes. Despite great progress in identifying many of the key host factors involved in the uptake of toxins, significant knowledge gaps remain as to how partially characterized and newly discovered microbial toxins exploit host factors or processes to intoxicate target cells. Proximity-dependent biotinylation (e.g., BioID) is a powerful method to identify nearby host factors in living cells, offering the potential to identify host targets of microbial toxins. Here, we used BioID to interrogate proximal interactors of the multi-domain <i>Clostridioides difficile</i> TcdB toxin. Expressed fusions of TurboID to different fragments of TcdB identified several high-confidence proteins in the cytosol, including members of the Rho GTPase signaling network and the actin cytoskeletal network. Additionally, we developed an extracellular proximity labeling method using recombinant TurboID-toxin chimeras, which uncovered a limited number of cell-surface targets including LRP1, which was previously identified as a cell-surface receptor of TcdB. Our work reveals surface receptors and intracellular components exploited by bacterial toxins, highlighting key vulnerabilities in host cells.IMPORTANCEBacterial toxins are the causative agents of many human diseases. Further characterizing the intoxication mechanisms of these proteins is important for the development of vaccines and treatments for toxin-mediated disease. Proximity-dependent biotinylation approaches offer an orthogonal approach to complement genetic screens. Here, we evaluate the potential of this method to identify host-toxin interactions on the cell surface and in the cytosol, where the toxin modifies essential host targets. Critically, we have highlighted several limitations of this method as applied to protein toxins, which are important for researchers to weigh when considering this technique for exotoxin studies.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0333624"},"PeriodicalIF":5.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11796423/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction for Hiramatsu et al., \"The Mechanism of Pertussis Cough Revealed by the Mouse-Coughing Model\".","authors":"Yukihiro Hiramatsu, Koichiro Suzuki, Takashi Nishida, Naoki Onoda, Takashi Satoh, Shizuo Akira, Masahito Ikawa, Hiroko Ikeda, Junzo Kamei, Sandra Derouiche, Makoto Tominaga, Yasuhiko Horiguchi","doi":"10.1128/mbio.03921-24","DOIUrl":"https://doi.org/10.1128/mbio.03921-24","url":null,"abstract":"","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0392124"},"PeriodicalIF":5.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189847","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}

{"title":"Gcn2 rescues reprogramming in the absence of Hog1/p38 signaling in <i>C. neoformans</i> during thermal stress.","authors":"David Goich, Amanda L M Bloom, Sean R Duffy, Maritza N Ventura, John C Panepinto","doi":"10.1128/mbio.01762-24","DOIUrl":"10.1128/mbio.01762-24","url":null,"abstract":"<p><p>The fungus <i>Cryptococcus neoformans</i> is an opportunistic pathogen of humans that reprograms its translatome to facilitate adaptation and virulence within the host. We studied the role of Hog1/p38 in reprogramming translation during thermal stress adaptation and found that this pathway acts on translation <i>via</i> crosstalk with the Gcn2 pathway, a well-studied regulator of general translation control. Using a combination of molecular assays and phenotypic analysis, we show that increased output from the Gcn2 pathway in a Hog1 deletion mutant is associated with rescue of thermal stress adaptation at both molecular and phenotypic scales. We characterize known outputs of the Hog1 pathway during thermal stress as either Gcn2-dependent or Gcn2-independent and demonstrate that Hog1 activation regulates the Gcn2 pathway even in the absence of thermal stress. Finally, we implicate this phenomenon in another Hog1-regulated process, morphogenesis, and recapitulate Hog1-Gcn2 crosstalk in the distantly related fungal pathogen, <i>Candida albicans</i>. Our results point to an important link between the stress response machinery and translation control and clarify the etiology of phenotypes associated with Hog1 deletion. More broadly, this study highlights complex interplay between core conserved signal transduction pathways and the utility of molecular assays to better understand how these pathways are connected.IMPORTANCE<i>Cryptococcus neoformans</i> is an opportunistic pathogen of humans that causes deadly cryptococcal meningitis, which is is responsible for an estimated 19% of AIDS-related mortality. When left untreated, cryptococcal meningitis is uniformly fatal, and in patients receiving the most effective antifungal regimens, mortality remains high. Thus, there is a critical need to identify additional targets that play a role in the adaptation to the human host and virulence. This study explores the role of the stress response kinases Hog1 and Gcn2 in thermoadaptation, which is a pre-requisite for virulence. Our results show that compensatory signaling occurs <i>via</i> the Gcn2 pathway when Hog1 is deleted, and that disruption of both pathways increases sensitivity to thermal stress. Importantly, our study highlights the insufficiency of using single-gene deletion mutants to study gene function, since many phenotypes associated with Hog1 deletion were driven by Gcn2 signaling in this background, rather than loss of direct Hog1 activity.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0176224"},"PeriodicalIF":5.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11796416/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}