PLoS Biology最新文献

{"title":"Structure of the scaffolding protein and portal within the bacteriophage P22 procapsid provides insights into the self-assembly process.","authors":"Hao Xiao, Wenyuan Chen, Hao Pang, Jing Zheng, Li Wang, Hao Feng, Jingdong Song, Lingpeng Cheng, Hongrong Liu","doi":"10.1371/journal.pbio.3003104","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003104","url":null,"abstract":"<p><p>In the assembly pathway of tailed double-stranded DNA (dsDNA) bacteriophages and herpesviruses, a procapsid with a dodecameric portal for DNA delivery at a unique vertex is initially formed. Appropriate procapsid assembly requires the transient presence of multiple copies of a scaffolding protein (SP), which is absent in the mature virion. However, how the SP contributes to dodecameric portal formation, facilitates portal and coat protein incorporation, and is subsequently released remains unclear because of a lack of structural information. Here, we present the structure of the SP-portal complex within the procapsid of bacteriophage P22 at 3-9 Å resolutions. The AlphaFold2-predicted SP model fits well with the density map of the complex. The SP forms trimers and tetramers that interact to yield a dome-like complex on the portal. Two SP domains mediate multimerization. Each trimer interacts with two neighboring portal subunits. The SP has a loop-hook-like structure that aids in coat protein recruitment during viral assembly. The loops of those SP subunits on the portal are positioned in clefts between adjacent portal subunits. Conformational changes in the portal during phage maturation may trigger the disassembly and release of the SP complex. Our findings provide insights into SP-assisted procapsid assembly in bacteriophage P22 and suggest that this strategy is also implemented by other dsDNA viruses, including herpesviruses.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003104"},"PeriodicalIF":9.8,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12005531/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144055380","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":"Applications and status of gene drive in plants.","authors":"Bruce A Hay","doi":"10.1371/journal.pbio.3003148","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003148","url":null,"abstract":"<p><p>Gene drive can modify or suppress plant populations, offering solutions to challenges associated with globalization and climate change. However, common features of plant biology complicate its application. Self-limiting methods provide a controlled, reversible path forward.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003148"},"PeriodicalIF":9.8,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12027107/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027059","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":"Monocyte-secreted Wnt reduces the efficiency of central nervous system remyelination.","authors":"Bianca M Hill, Rebecca K Holloway, Lindsey H Forbes, Claire L Davies, Jonathan K Monteiro, Christina M Brown, Jamie Rose, Neva Fudge, Pamela J Plant, Ayisha Mahmood, Koroboshka Brand-Arzamendi, Sarah A Kent, Irene Molina-Gonzalez, Stefka Gyoneva, Richard M Ransohoff, Brian Wipke, Josef Priller, Raphael Schneider, Craig S Moore, Veronique E Miron","doi":"10.1371/journal.pbio.3003073","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003073","url":null,"abstract":"<p><p>The regeneration of myelin in the central nervous system (CNS) reinstates nerve health and function, yet its decreased efficiency with aging and progression of neurodegenerative disease contributes to axonal loss and/or degeneration. Although CNS myeloid cells have been implicated in regulating the efficiency of remyelination, the distinct contribution of blood monocytes versus that of resident microglia is unclear. Here, we reveal that monocytes have non-redundant functions compared to microglia in regulating remyelination. Using a transgenic mouse in which classical monocytes have reduced egress from bone marrow (Ccr2-/-), we demonstrate that monocytes drive the timely onset of oligodendrocyte differentiation and myelin protein expression, yet impede myelin production. Ribonucleic acid sequencing revealed a Wnt signature in wild-type mouse lesion monocytes, which was confirmed in monocytes from multiple sclerosis white matter lesions and blood. Genetic or pharmacological inhibition of Wnt release by monocytes increased remyelination. Our findings reveal monocytes to be critical regulators of remyelination and identify monocytic Wnt signaling as a promising therapeutic target to inhibit for increased efficiency of CNS regeneration.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003073"},"PeriodicalIF":9.8,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12052099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144021223","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":"How did vocal communication come to dominate human language? A view from the womb.","authors":"Alexis Hervais-Adelman, Simon W Townsend","doi":"10.1371/journal.pbio.3003141","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003141","url":null,"abstract":"<p><p>Whether human language evolved via a gestural or a vocal route remains an unresolved and contentious issue. Given the existence of two preconditions-a \"language faculty\" and the capacity for imitative learning both vocally and manually-there is no compelling evidence for gesture being inherently inferior to vocalization as a mode of linguistic expression; indeed, signed languages are capable of the same expressive range as spoken ones. Here, we revisit this conundrum, championing recent methodological advances in human neuroimaging (specifically, in utero functional magnetic resonance imaging) as a window into the role of the prenatal gestational period in language evolution, a critical, yet currently underexplored environment in which fetuses are exposed to, and become attuned to, spoken language. In this Unsolved Mystery, we outline how, compared to visual sensitivity, the ontogenically earlier development of auditory sensitivity, beginning in utero and persisting for several months post-partum, alongside the relative permeability of the uterine environment to sound, but not light, may constitute a small but significant contribution to the current dominance of spoken language.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003141"},"PeriodicalIF":9.8,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12021287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144053795","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":"The G protein modifier KCTD5 tunes the decoding of neuromodulatory signals necessary for motor function in striatal neurons.","authors":"Douglas C Sloan, Yini Liao, Forest Ray, Brian S Muntean","doi":"10.1371/journal.pbio.3003117","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003117","url":null,"abstract":"<p><p>G proteins (Gα and Gβγ subtypes) drive adenylyl cyclase type 5 (AC5) synthesis of cAMP in striatal neurons, which is essential for motor coordination. KCTD5 directly interacts with Gβγ to delimit signaling events, yet downstream impact of KCTD5 in striatal circuits is not known. Here, generation of a conditional Kctd5 knockout mouse identified that loss of striatal KCTD5 leads to a dystonic phenotype, coordination deficits, and skewed transitions between behavioral syllables. 2-photon imaging of a cAMP biosensor revealed electrically evoked dopaminergic responses were significantly augmented in the absence of KCTD5 in striatal circuits. cAMP sensitization was rescued in situ by expression of a Gβγ-scavenging nanobody and motor deficits were partially rescued in vivo by pharmacological antagonism of the indirect striatal cAMP pathway. Therefore, KCTD5 acts as a brake on cAMP signaling in striatal neurons important for tuning dopaminergic signaling and motor coordination.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003117"},"PeriodicalIF":9.8,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12021292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144064394","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":"Expanding the bat toolbox: Carollia perspicillata bat cell lines and reagents enable the characterization of viral susceptibility and innate immune responses.","authors":"Victoria Gonzalez, Cierra Word, Nahomi Guerra-Pilaquinga, Mitra Mazinani, Stephen Fawcett, Christine Portfors, Darryl Falzarano, Alison M Kell, Rohit K Jangra, Arinjay Banerjee, Stephanie N Seifert, Michael Letko","doi":"10.1371/journal.pbio.3003098","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003098","url":null,"abstract":"<p><p>Multiple viruses that are highly pathogenic in humans are known to have evolved in bats. How bats tolerate infection with these viruses, however, is poorly understood. As viruses engage in a wide range of interactions with their hosts, it is essential to study bat viruses in a system that resembles their natural environment like bat-derived in vitro cellular models. However, stable and accessible bat cell lines are not widely available for the broader scientific community. Here, we generated in vitro reagents for the Seba's short-tailed bat (Carollia perspicillata), tested multiple methods of immortalization, and characterized their susceptibility to virus infection and response to immune stimulation. Using pseudotyped virus library and authentic virus infections, we show that these C. perspicillata cell lines derived from a diverse array of tissues are susceptible to viruses bearing the glycoprotein of numerous orthohantaviruses, including Andes and Hantaan virus and are also susceptible to live hantavirus infection. Furthermore, stimulation with synthetic double-stranded RNA prior to infection with vesicular stomatitis virus and Middle Eastern respiratory syndrome coronavirus induced a protective antiviral response, demonstrating the suitability of our cell lines to study the bat antiviral immune response. Taken together, the approaches outlined here will inform future efforts to develop in vitro tools for virology from non-model organisms and these C. perspicillata cell lines will enable studies on virus-host interactions in these bats.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003098"},"PeriodicalIF":9.8,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11999112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144062826","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":"Structures of G-protein coupled receptor HCAR1 in complex with Gi1 protein reveal the mechanistic basis for ligand recognition and agonist selectivity.","authors":"Xin Pan, Fang Ye, Peiruo Ning, Yiping Yu, Zhiyi Zhang, Jingxuan Wang, Geng Chen, Zhangsong Wu, Chen Qiu, Jiancheng Li, Bangning Chen, Lizhe Zhu, Chungen Qian, Kaizheng Gong, Yang Du","doi":"10.1371/journal.pbio.3003126","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003126","url":null,"abstract":"<p><p>Hydroxycarboxylic acid receptor 1 (HCAR1), also known as lactate receptor or GPR81, is a class A G-protein-coupled receptor with key roles in regulating lipid metabolism, neuroprotection, angiogenesis, cardiovascular function, and inflammatory response in humans. HCAR1 is highly expressed in numerous types of cancer cells, where it participates in controlling cancer cell metabolism and defense mechanisms, rendering it an appealing target for cancer therapy. However, the molecular basis of HCAR1-mediated signaling remains poorly understood. Here, we report four cryo-EM structures of human HCAR1 and HCAR2 in complex with the Gi1 protein, in which HCAR1 binds to the subtype-specific agonist CHBA (3.16 Å) and apo form (3.36 Å), and HCAR2 binds to the subtype-specific agonists MK-1903 (2.68 Å) and SCH900271 (3.06 Å). Combined with mutagenesis and cellular functional assays, we elucidate the mechanisms underlying ligand recognition, receptor activation, and G protein coupling of HCAR1. More importantly, the key residues that determine ligand selectivity between HCAR1 and HCAR2 are clarified. On this basis, we further summarize the structural features of agonists that match the orthosteric pockets of HCAR1 and HCAR2. These structural insights are anticipated to greatly accelerate the development of novel HCAR1-targeted drugs, offering a promising avenue for the treatment of various diseases.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003126"},"PeriodicalIF":9.8,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12040280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144004619","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":"Transcriptomic atlas throughout Coccidioides development reveals key phase-enriched transcripts of this important fungal pathogen.","authors":"Christina M Homer, Mark Voorhies, Keith Walcott, Elena Ochoa, Anita Sil","doi":"10.1371/journal.pbio.3003066","DOIUrl":"10.1371/journal.pbio.3003066","url":null,"abstract":"<p><p>Coccidioides spp. are highly understudied but significant dimorphic fungal pathogens that can infect both immunocompetent and immunocompromised people. In the environment, they grow as multicellular filaments (hyphae) that produce vegetative spores called arthroconidia. Upon inhalation by mammals, arthroconidia undergo a process called spherulation. They enlarge and undergo numerous nuclear divisions to form a spherical structure, and then internally segment until the spherule is filled with multiple cells called endospores. Mature spherules rupture and release endospores, each of which can form another spherule, in a process thought to facilitate dissemination. Spherulation is unique to Coccidioides, and its molecular determinants remain largely unknown. Here, we report the first high-density transcriptomic analyses of Coccidioides development, defining morphology-dependent transcripts and those whose expression is regulated by RYP1, a major regulator required for spherulation and virulence. Of approximately 9,000 predicted transcripts, we discovered 273 transcripts with consistent spherule-associated expression, 82 of which are RYP1-dependent, a set likely to be critical for Coccidioides virulence. ChIP-Seq revealed two distinct regulons of Ryp1: one shared between hyphae and spherules and the other unique to spherules. Spherulation regulation was elaborate, with the majority of 227 predicted transcription factors in Coccidioides displaying spherule-enriched expression. We identified provocative targets, including 20 transcripts whose expression is endospore-enriched and 14 putative secreted effectors whose expression is spherule-enriched, of which six are secreted proteases. To highlight the utility of these data, we selected a cluster of Ryp1-dependent, arthroconidia-associated transcripts and found that they play a role in arthroconidia cell wall biology, demonstrating the power of this resource in illuminating Coccidioides biology and virulence.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003066"},"PeriodicalIF":9.8,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144042688","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 the ultrastructural topology of the corynebacterial cell surface.","authors":"Buse Isbilir, Anna Yeates, Vikram Alva, Tanmay A M Bharat","doi":"10.1371/journal.pbio.3003130","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003130","url":null,"abstract":"<p><p>Corynebacterium glutamicum is a diderm bacterium extensively used in the industrial-scale production of amino acids. Corynebacteria belong to the bacterial family Mycobacteriaceae, which is characterized by a highly unusual cell envelope with an outer membrane consisting of mycolic acids, called mycomembrane. The mycomembrane is further coated by a surface (S-)layer array in C. glutamicum, making this cell envelope highly distinctive. Despite the biotechnological significance of C. glutamicum and biomedical significance of mycomembrane-containing pathogens, ultrastructural and molecular details of its distinctive cell envelope remain poorly characterized. To address this, we investigated the cell envelope of C. glutamicum using electron cryotomography and cryomicroscopy of focused ion beam-milled single and dividing cells. Our cellular imaging allowed us to map the different components of the cell envelope onto the tomographic density. Our data reveal that C. glutamicum has a variable cell envelope, with the S-layer decorating the mycomembrane in a patchy manner. We further isolated and resolved the structure of the S-layer at 3.1 Å-resolution using single particle electron cryomicroscopy. Our structure shows that the S-layer of C. glutamicum is composed of a hexagonal array of the PS2 protein, which interacts directly with the mycomembrane via an anchoring segment containing a coiled-coil motif. Bioinformatic analyses revealed that the PS2 S-layer is sparsely yet exclusively present within the Corynebacterium genus and absent in other genera of the Mycobacteriaceae family, suggesting distinct evolutionary pathways in the development of their cell envelopes. Our structural and cellular data collectively provide a topography of the unusual C. glutamicum cell surface, features of which are shared by many pathogenic and microbiome-associated bacteria, as well as by several industrially significant bacterial species.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003130"},"PeriodicalIF":9.8,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12021427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144048113","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":"Staphylococcal toxin PVL ruptures model membranes under acidic conditions through interactions with cardiolipin and phosphatidic acid.","authors":"Seong H Chow, Yusun Jeon, Pankaj Deo, Amy T Y Yeung, Christine Hale, Sushmita Sridhar, Gilu Abraham, Joshua Nickson, Françios A B Olivier, Jhih-Hang Jiang, Yue Ding, Mei-Ling Han, Anton P Le Brun, Dovile Anderson, Darren Creek, Janette Tong, Kip Gabriel, Jian Li, Ana Traven, Gordon Dougan, Hsin-Hui Shen, Thomas Naderer","doi":"10.1371/journal.pbio.3003080","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003080","url":null,"abstract":"<p><p>Panton-Valentine leukocidin (PVL) is a pore-forming toxin secreted by Staphylococcus aureus strains that cause severe infections. Bicomponent PVL kills phagocytes depending on cell surface receptors, such as complement 5a receptor 1 (C5aR1). How the PVL-receptor interaction enables assembly of the leukocidin complex, targeting of membranes, and insertion of a pore channel remains incompletely understood. Here, we demonstrate that PVL binds the anionic phospholipids, phosphatidic acid, and cardiolipin, under acidic conditions and targets lipid bilayers that mimic lysosomal and mitochondrial membranes, but not the plasma membrane. The PVL-lipid interaction was sufficient to enable leukocidin complex formation as determined by neutron reflectometry and the rupture of model membranes, independent of protein receptors. In phagocytes, PVL and its C5aR1 receptor were internalized depending on sphingomyelin and cholesterol, which were dispensable for the interaction of the toxin with the plasma membrane. Internalized PVL compromised the integrity of lysosomes and mitochondria before plasma membrane rupture. Preventing the acidification of organelles or the genetic loss of PVL impaired the escape of intracellular S. aureus from macrophages. Together, the findings advance our understanding of how an S. aureus toxin kills host cells and provide key insights into how leukocidins target membranes.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003080"},"PeriodicalIF":9.8,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12052211/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144055079","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}