PLoS Biology最新文献

{"title":"The HCF101 protein is an important component of the cytosolic iron-sulfur synthesis pathway in Toxoplasma gondii.","authors":"Eléa A Renaud, Ambre J M Maupin, Laurence Berry, Julie Bals, Yann Bordat, Vincent Demolombe, Valérie Rofidal, Florence Vignols, Sébastien Besteiro","doi":"10.1371/journal.pbio.3003028","DOIUrl":"10.1371/journal.pbio.3003028","url":null,"abstract":"<p><p>Several key cellular functions depend on proteins harboring an iron-sulfur (Fe-S) cofactor. As these Fe-S proteins localize to several subcellular compartments, they require a dedicated machinery for cofactor assembly. For instance, in plants and algae there are Fe-S cluster synthesis pathways localizing to the cytosol, but also present in the mitochondrion and in the chloroplast, 2 organelles of endosymbiotic origin. Toxoplasma gondii is a plastid-bearing parasitic protist responsible for a pathology affecting humans and other warm-blooded vertebrates. We have characterized the Toxoplasma homolog of HCF101, originally identified in plants as a protein transferring Fe-S clusters to photosystem I subunits in the chloroplast. Contrarily to plants, we have shown that HCF101 does not localize to the plastid in parasites, but instead is an important component of the cytosolic Fe-S assembly (CIA) pathway which is vital for Toxoplasma. While the CIA pathway is widely conserved in eukaryotes, it is the first time the involvement of HCF101 in this pan-eukaryotic machinery is established. Moreover, as this protein is essential for parasite viability and absent from its mammalian hosts, it constitutes a novel and promising potential drug target.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 2","pages":"e3003028"},"PeriodicalIF":9.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11838916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143366574","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 placenta as a cradle, but not source, of blood?","authors":"Julie Y Chen, Kyle M Loh","doi":"10.1371/journal.pbio.3003021","DOIUrl":"10.1371/journal.pbio.3003021","url":null,"abstract":"<p><p>An important question is whether the placenta is a source of, or merely a niche for, blood-forming hematopoietic stem cells. A recent PLOS Biology study suggests that the placenta does not directly give rise to hematopoietic stem cells.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 2","pages":"e3003021"},"PeriodicalIF":9.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11801694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365098","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 exocytosis regulator complexin controls spontaneous synaptic vesicle release in a CAPS-dependent manner at C. elegans excitatory synapses.","authors":"Ya Wang, Chun Hin Chow, Yu Zhang, Mengjia Huang, Randa Higazy, Neeraja Ramakrishnan, Lili Chen, Xuhui Chen, Yixiang Deng, Sheng Wang, Cuntai Zhang, Cong Ma, Shuzo Sugita, Shangbang Gao","doi":"10.1371/journal.pbio.3003023","DOIUrl":"10.1371/journal.pbio.3003023","url":null,"abstract":"<p><p>The balance between synaptic excitation and inhibition (E/I) is essential for coordinating motor behavior, yet the differential roles of exocytosis regulators in this balance are less understood. In this study, we investigated the roles of 2 conserved exocytosis regulators, complexin/CPX-1 and CAPS/UNC-31, in excitatory versus inhibitory synapses at Caenorhabditis elegans neuromuscular junctions. cpx-1 null mutants exhibited a marked increase in spontaneous release specifically at excitatory synapses, alongside an unequal reduction in excitatory and inhibitory evoked release. A clamping-specific knockin mutant, cpx-1(Δ12), which preserved evoked release, also showed a biased enhancement in excitatory spontaneous release. Conversely, the unc-31 null mutation, while maintaining normal spontaneous release, displayed a more pronounced reduction in evoked release at excitatory synapses. Notably, we found that CPX-1's clamping function is dependent on UNC-31 and is sensitive to external Ca2+. Pull-down experiments confirmed that CAPS/UNC-31 does not directly interact with complexin, implying an indirect regulatory mechanism. Moreover, complexin regulates activity-dependent synaptic plasticity, which is also UNC-31 dependent. The unexpected role of CAPS/UNC-31 in the absence of CPX-1 clamping function may underpin the synaptic E/I balance and coordinated behavioral outputs in different species.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 2","pages":"e3003023"},"PeriodicalIF":9.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11838871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143366570","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":"mRNA stability fine-tunes gene expression in the developing cortex to control neurogenesis.","authors":"Lucas D Serdar, Jacob R Egol, Brad Lackford, Brian D Bennett, Guang Hu, Debra L Silver","doi":"10.1371/journal.pbio.3003031","DOIUrl":"10.1371/journal.pbio.3003031","url":null,"abstract":"<p><p>RNA abundance is controlled by rates of synthesis and degradation. Although mis-regulation of RNA turnover is linked to neurodevelopmental disorders, how it contributes to cortical development is largely unknown. Here, we discover the landscape of RNA stability regulation in the cerebral cortex and demonstrate that intact RNA decay machinery is essential for corticogenesis in vivo. We use SLAM-seq to measure RNA half-lives transcriptome-wide across multiple stages of cortical development. Leveraging these data, we discover cis-acting features associated with RNA stability and probe the relationship between RNA half-life and developmental expression changes. Notably, RNAs that are up-regulated across development tend to be more stable, while down-regulated RNAs are less stable. Using compound mouse genetics, we discover CNOT3, a core component of the CCR4-NOT deadenylase complex linked to neurodevelopmental disease, is essential for cortical development. Conditional knockout of Cnot3 in neural progenitors and their progeny in the developing mouse cortex leads to severe microcephaly due to altered cell fate and p53-dependent apoptosis. Finally, we define the molecular targets of CNOT3, revealing it controls expression of poorly expressed, non-optimal mRNAs in the cortex, including cell cycle-related transcripts. Collectively, our findings demonstrate that fine-tuned control of RNA turnover is crucial for brain development.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 2","pages":"e3003031"},"PeriodicalIF":9.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11838918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143366627","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":"HCNetlas: A reference database of human cell type-specific gene networks to aid disease genetic analyses.","authors":"Jiwon Yu, Junha Cha, Geon Koh, Insuk Lee","doi":"10.1371/journal.pbio.3002702","DOIUrl":"10.1371/journal.pbio.3002702","url":null,"abstract":"<p><p>Cell type-specific actions of disease genes add a significant layer of complexity to the genetic architecture underlying diseases, obscuring our understanding of disease mechanisms. Single-cell omics have revealed the functional roles of genes at the cellular level, identifying cell types critical for disease progression. Often, a gene impact on disease through its altered network within specific cell types, rather than mere changes in expression levels. To explore the cell type-specific roles of disease genes, we developed HCNetlas (human cell network atlas), a resource cataloging cell type-specific gene networks (CGNs) for various healthy tissue cells. We also devised 3 network analysis methods to investigate cell type-specific functions of disease genes. These methods involve comparing HCNetlas CGNs with those derived from disease-affected tissue samples. These methods find that systemic lupus erythematosus genes predominantly function in myeloid cells, and Alzheimer's disease genes mainly play roles in inhibitory and excitatory neurons. Additionally, they suggest that many lung cancer-related genes may exert their roles in immune cells. These findings suggest that HCNetlas has the potential to link disease-associated genes to cell types of action, facilitating development of cell type-resolved diagnostics and therapeutic strategies for complex human diseases.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 2","pages":"e3002702"},"PeriodicalIF":9.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11798474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256757","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":"Bacteriocin-like peptides encoded by a horizontally acquired island mediate Neisseria gonorrhoeae autolysis.","authors":"Katy Poncin, Samantha A McKeand, Hayley Lavender, Kacper Kurzyp, Odile B Harrison, Annabell Roberti, Charlotte Melia, Errin Johnson, Martin C J Maiden, David R Greaves, Rachel Exley, Christoph M Tang","doi":"10.1371/journal.pbio.3003001","DOIUrl":"10.1371/journal.pbio.3003001","url":null,"abstract":"<p><p>Neisseria gonorrhoeae is a human-specific pathogen that causes the important sexually transmitted infection, gonorrhoea, an inflammatory condition of the genitourinary tract. The bacterium is closely related to the meningococcus, a leading cause of bacterial meningitis. Both these invasive bacterial species undergo autolysis when in the stationary phase of growth. Autolysis is a form of programmed cell death (PCD) which is part of the life cycle of remarkably few bacteria and poses an evolutionary conundrum as altruistic death provides no obvious benefit for single-celled organisms. Here, we searched for genes present in these 2 invasive species but not in other members of the Neisseria genus. We identified a ~3.4 kb horizontally acquired region, we termed the nap island, which is largely restricted to the gonococcus and meningococcus. The nap island in the gonococcus encodes 3 cationic, bacteriocin-like peptides which have no detectable antimicrobial activity. Instead, the gonococcal Neisseria autolysis peptides (Naps) promote autolytic cell death when bacteria enter the stationary phase of growth. Furthermore, strains lacking the Naps exhibit reduced autolysis in assays of PCD. Expression of Naps is likely to be phase variable, explaining how PCD could have arisen in these important human pathogens. NapC also induces lysis of human cells, so the peptides are likely to have multiple roles during colonisation and disease. The acquisition of the nap island contributed to the emergence of PCD in the gonococcus and meningococcus and potentially to the appearance of invasive disease in Neisseria spp.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 2","pages":"e3003001"},"PeriodicalIF":9.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11798529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256547","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":"Shallow seamounts are \"oases\" and activity hubs for pelagic predators in a large-scale marine reserve.","authors":"Sam B Weber, Andrew J Richardson, Christopher D H Thompson, Judith Brown, Fabio Campanella, Brendan J Godley, Nigel E Hussey, Jessica J Meeuwig, Paul Rose, Nicola Weber, Matthew J Witt, Annette C Broderick","doi":"10.1371/journal.pbio.3003016","DOIUrl":"10.1371/journal.pbio.3003016","url":null,"abstract":"<p><p>Seamounts have been likened to \"oases\" of life in the comparative deserts of the open ocean, often harbouring high densities of threatened and exploited pelagic top predators. However, few such aggregations have been studied in any detail and the mechanisms that sustain them are poorly understood. Here, we present the findings of an integrated study of 3 previously unexplored seamounts in the tropical Atlantic, which aimed to investigate their significance as predator \"hotspots\" and inform their inclusion in one of world's largest marine reserves. Baited underwater video and visual census transects revealed enhanced diversity and biomass of pelagic top predators, including elevated abundances of 7 species of sharks, predatory fish, and seabirds, within 5 km of 2 shallow seamounts (<100 m), but not a third deeper seamount (260 m). Hydroacoustic biomass of low- and mid-trophic level \"prey\" was also significantly elevated within 2.5 km of shallow seamounts. However, we found no evidence of enhanced primary productivity over any feature, suggesting high faunal biomass is sustained by exogenous energy inputs. Relative biomass enrichment also increased with trophic level, ranging from a 2-fold increase for zooplankton to a 41-fold increase for sharks. Tracking of the dominant predator species revealed that individual sharks (Galapagos, silky) and tuna (yellowfin, bigeye) often resided around seamounts for months to years, with evidence of connectivity between features, and (in the case of sharks) were spatially aggregated in localised hotspots that coincided with areas of high mid-trophic biomass. However, tuna and silky sharks also appeared to use seamounts as \"hubs\" in more extensive pelagic foraging ranges, which may help explain disproportionately high predator density. Our results reinforce the conservation significance of shallow seamounts for many marine top predators and offer fundamental insights into their functional roles as both prey \"oases\" and activity hubs for these species.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 2","pages":"e3003016"},"PeriodicalIF":9.8,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11828362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190849","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":"VANGL2 alleviates inflammatory bowel disease by recruiting the ubiquitin ligase MARCH8 to limit NLRP3 inflammasome activation through OPTN-mediated selective autophagy.","authors":"Huaji Jiang, Yingchao Xie, Zhiqiang Hu, Jiansen Lu, Jiahuan Zhang, Hongyu Li, Ke Zeng, Wenqiang Peng, Cheng Yang, Junsheng Huang, Zelong Han, Xiaochun Bai, Xiao Yu","doi":"10.1371/journal.pbio.3002961","DOIUrl":"10.1371/journal.pbio.3002961","url":null,"abstract":"<p><p>Inflammatory bowel disease (IBD) is a chronic and potentially life-threatening inflammatory disease of gastroenteric tissue characterized by episodes of intestinal inflammation, but the underlying mechanisms remain elusive. Here, we explore the role and precise mechanism of Van-Gogh-like 2 (VANGL2) during the pathogenesis of IBD. VANGL2 decreases in IBD patients and dextran sulfate sodium (DSS)-induced colitis in mice. Myeloid VANGL2 deficiency exacerbates the progression of DSS-induced colitis in mice and specifically enhances the activation of NLRP3 inflammasome in macrophages. NLRP3-specific inhibitor MCC950 effectively alleviates DSS-induced colitis in VANGL2 deficient mice. Mechanistically, VANGL2 interacts with NLRP3 and promotes the autophagic degradation of NLRP3 through enhancing the K27-linked polyubiquitination at lysine 823 of NLRP3 by recruiting E3 ligase MARCH8, leading to optineurin (OPTN)-mediated selective autophagy. Notably, decreased VANGL2 in the peripheral blood mononuclear cells from IBD patients results in overt NLRP3 inflammasome activation and sustained inflammation. Taken together, this study demonstrates that VANGL2 acts as a repressor of IBD progression by inhibiting NLRP3 inflammasome activation and provides insights into the crosstalk between inflammation and autophagy in preventing IBD.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 2","pages":"e3002961"},"PeriodicalIF":9.8,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11790156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123870","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":"Detailed characterisation of the trypanosome nuclear pore architecture reveals conserved asymmetrical functional hubs that drive mRNA export.","authors":"Bernardo Papini Gabiatti, Johanna Krenzer, Silke Braune, Timothy Krüger, Martin Zoltner, Susanne Kramer","doi":"10.1371/journal.pbio.3003024","DOIUrl":"10.1371/journal.pbio.3003024","url":null,"abstract":"<p><p>Nuclear export of mRNAs requires loading the mRNP to the transporter Mex67/Mtr2 in the nucleoplasm, controlled access to the pore by the basket-localised TREX-2 complex and mRNA release at the cytoplasmic site by the DEAD-box RNA helicase Dbp5. Asymmetric localisation of nucleoporins (NUPs) and transport components as well as the ATP dependency of Dbp5 ensure unidirectionality of transport. Trypanosomes possess homologues of the mRNA transporter Mex67/Mtr2, but not of TREX-2 or Dbp5. Instead, nuclear export is likely fuelled by the GTP/GDP gradient created by the Ran GTPase. However, it remains unclear, how directionality is achieved since the current model of the trypanosomatid pore is mostly symmetric. We have revisited the architecture of the trypanosome nuclear pore complex using a novel combination of expansion microscopy, proximity labelling and streptavidin imaging. We could confidently assign the NUP76 complex, a known Mex67 interaction platform, to the cytoplasmic site of the pore and the NUP64/NUP98/NUP75 complex to the nuclear site. Having defined markers for both sites of the pore, we set out to map all 75 trypanosome proteins with known nuclear pore localisation to a subregion of the pore using mass spectrometry data from proximity labelling. This approach defined several further proteins with a specific localisation to the nuclear site of the pore, including proteins with predicted structural homology to TREX-2 components. We mapped the components of the Ran-based mRNA export system to the nuclear site (RanBPL), the cytoplasmic site (RanGAP, RanBP1) or both (Ran, MEX67). Lastly, we demonstrate, by deploying an auxin degron system, that NUP76 holds an essential role in mRNA export consistent with a possible functional orthology to NUP82/88. Altogether, the combination of proximity labelling with expansion microscopy revealed an asymmetric architecture of the trypanosome nuclear pore supporting inherent roles for directed transport. Our approach delivered novel nuclear pore associated components inclusive positional information, which can now be interrogated for functional roles to explore trypanosome-specific adaptions of the nuclear basket, export control, and mRNP remodelling.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 2","pages":"e3003024"},"PeriodicalIF":9.8,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11825100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123898","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":"Tonic ubiquitination of the central body weight regulator melanocortin receptor 4 (MC4R) promotes its constitutive exit from cilia.","authors":"Irene Ojeda-Naharros, Tirthasree Das, Ralph A Castro, J Fernando Bazan, Christian Vaisse, Maxence V Nachury","doi":"10.1371/journal.pbio.3003025","DOIUrl":"10.1371/journal.pbio.3003025","url":null,"abstract":"<p><p>The G protein-coupled receptor (GPCR) melanocortin receptor 4 (MC4R) is an essential regulator of body weight homeostasis. MC4R is unusual among GPCRs in that its activity is regulated by 2 opposing physiological ligands, the agonist ⍺-MSH and the antagonist/inverse agonist AgRP. Paradoxically, while MC4R localizes and functions at the cilium of hypothalamic neurons, the ciliary levels of MC4R are very low under unrestricted feeding conditions. Here, we find that the constitutive activity of MC4R is responsible for the continuous depletion of MC4R from cilia and that inhibition of MC4R's activity via AgRP leads to a robust accumulation of MC4R in cilia. Ciliary targeting of MC4R is mediated by its partner MRAP2 and the constitutive exit of MC4R from cilia relies on the sensor of activation β-arrestin, on ubiquitination, and on the BBSome ciliary trafficking complex. Thus, while MC4R exits cilia via conventional mechanisms, it only accumulates in cilia when its activity is suppressed by AgRP.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 2","pages":"e3003025"},"PeriodicalIF":9.8,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11825094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123868","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}