{"title":"The transcription factor RUNT-like regulates pupal cuticle development via promoting a pupal cuticle protein transcription","authors":"Ke-Yan Jin, Xiao-Pei Wang, Yu-Qin Di, Yu-Meng Zhao, Jin-Xing Wang, Xiao-Fan Zhao","doi":"10.1371/journal.pgen.1011393","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011393","url":null,"abstract":"Holometabolous insects undergo morphological remodeling from larvae to pupae and to adults with typical changes in the cuticle; however, the mechanism is unclear. Using the lepidopteran agricultural insect <jats:italic>Helicoverpa armigera</jats:italic>, cotton bollworm, as a model, we revealed that the transcription factor RUNT-like (encoded by <jats:italic>Runt-like</jats:italic>) regulates the development of the pupal cuticle via promoting a pupal cuticle protein gene (<jats:italic>HaPcp</jats:italic>) expression. The <jats:italic>HaPcp</jats:italic> was highly expressed in the epidermis and wing during metamorphosis and was found being involved in pupal cuticle development by RNA interference (RNAi) analysis in larvae. <jats:italic>Runt-like</jats:italic> was also strongly upregulated in the epidermis and wing during metamorphosis. Knockdown of <jats:italic>Runt-like</jats:italic> produced similar phenomena, a failure of abdomen yellow envelope and wing formation, to those following <jats:italic>HaPcp</jats:italic> knockdown. The insect molting hormone 20-hydroxyecdysonen (20E) upregulated <jats:italic>HaPcp</jats:italic> transcription via RUNT-like. 20E upregulated <jats:italic>Runt-like</jats:italic> transcription via nuclear receptor EcR and the transcription factor FOXO. Together, RUNT-like and HaPCP are involved in pupal cuticle development during metamorphosis under 20E regulation.","PeriodicalId":20266,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Subfunctionalization of NRC3 altered the genetic structure of the Nicotiana NRC network","authors":"Ching-Yi Huang, Yu-Seng Huang, Yu Sugihara, Hung-Yu Wang, Lo-Ting Huang, Juan Carlos Lopez-Agudelo, Yi-Feng Chen, Kuan-Yu Lin, Bing-Jen Chiang, AmirAli Toghani, Jiorgos Kourelis, Chun-Hsiung Wang, Lida Derevnina, Chih-Hang Wu","doi":"10.1371/journal.pgen.1011402","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011402","url":null,"abstract":"Nucleotide-binding domain and leucine-rich repeat (NLR) proteins play crucial roles in immunity against pathogens in both animals and plants. In solanaceous plants, activation of several sensor NLRs triggers their helper NLRs, known as NLR-required for cell death (NRC), to form resistosome complexes to initiate immune responses. While the sensor NLRs and downstream NRC helpers display diverse genetic compatibility, molecular evolutionary events leading to the complex network architecture remained elusive. Here, we showed that solanaceous NRC3 variants underwent subfunctionalization after the divergence of <jats:italic>Solanum</jats:italic> and <jats:italic>Nicotiana</jats:italic>, altering the genetic architecture of the NRC network in <jats:italic>Nicotiana</jats:italic>. Natural solanaceous NRC3 variants form three allelic groups displaying distinct compatibilities with the sensor NLR Rpi-blb2. Ancestral sequence reconstruction and analyses of natural and chimeric variants identified six key amino acids involved in sensor-helper compatibility. These residues are positioned on multiple surfaces of the resting NRC3 homodimer, collectively contributing to their compatibility with Rpi-blb2. Upon activation, Rpi-blb2-compatible NRC3 variants form membrane-associated punctate and high molecular weight complexes, and confer resistance to the late blight pathogen <jats:italic>Phytophthora infestans</jats:italic>. Our findings revealed how mutations in NRC alleles lead to subfunctionalization, altering sensor-helper compatibility and contributing to the increased complexity of the NRC network.","PeriodicalId":20266,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2024-09-11DOI: 10.1371/journal.pgen.1011093
Deema Ali, Aodán Laighneach, Emma Corley, Saahithh Redddi Patlola, Rebecca Mahoney, Laurena Holleran, Declan P. McKernan, John P. Kelly, Aiden P. Corvin, Brian Hallahan, Colm McDonald, Gary Donohoe, Derek W. Morris
{"title":"Direct targets of MEF2C are enriched for genes associated with schizophrenia and cognitive function and are involved in neuron development and mitochondrial function","authors":"Deema Ali, Aodán Laighneach, Emma Corley, Saahithh Redddi Patlola, Rebecca Mahoney, Laurena Holleran, Declan P. McKernan, John P. Kelly, Aiden P. Corvin, Brian Hallahan, Colm McDonald, Gary Donohoe, Derek W. Morris","doi":"10.1371/journal.pgen.1011093","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011093","url":null,"abstract":"<jats:italic>Myocyte Enhancer Factor 2C</jats:italic> (<jats:italic>MEF2C</jats:italic>) is a transcription factor that plays a crucial role in neurogenesis and synapse development. Genetic studies have identified <jats:italic>MEF2C</jats:italic> as a gene that influences cognition and risk for neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia (SCZ). Here, we investigated the involvement of <jats:italic>MEF2C</jats:italic> in these phenotypes using human-derived neural stem cells (NSCs) and glutamatergic induced neurons (iNs), which represented early and late neurodevelopmental stages. For these cellular models, <jats:italic>MEF2C</jats:italic> function had previously been disrupted, either by direct or indirect mutation, and gene expression assayed using RNA-seq. We integrated these RNA-seq data with <jats:italic>MEF2C</jats:italic> ChIP-seq data to identify dysregulated direct target genes of <jats:italic>MEF2C</jats:italic> in the NSCs and iNs models. Several <jats:italic>MEF2C</jats:italic> direct target gene-sets were enriched for SNP-based heritability for intelligence, educational attainment and SCZ, as well as being enriched for genes containing rare <jats:italic>de novo</jats:italic> mutations reported in ASD and/or developmental disorders. These gene-sets are enriched in both excitatory and inhibitory neurons in the prenatal and adult brain and are involved in a wide range of biological processes including neuron generation, differentiation and development, as well as mitochondrial function and energy production. We observed a trans expression quantitative trait locus (eQTL) effect of a single SNP at <jats:italic>MEF2C</jats:italic> (rs6893807, which is associated with IQ) on the expression of a target gene, <jats:italic>BNIP3L</jats:italic>. <jats:italic>BNIP3L</jats:italic> is a prioritized risk gene from the largest genome-wide association study of SCZ and has a function in mitophagy in mitochondria. Overall, our analysis reveals that either direct or indirect disruption of <jats:italic>MEF2C</jats:italic> dysregulates sets of genes that contain multiple alleles associated with SCZ risk and cognitive function and implicates neuron development and mitochondrial function in the etiology of these phenotypes.","PeriodicalId":20266,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2024-09-11DOI: 10.1371/journal.pgen.1011406
Holly J. Thorpe, Raghavendran Partha, Jordan Little, Nathan L. Clark, Clement Y. Chow
{"title":"Evolutionary rate covariation is pervasive between glycosylation pathways and points to potential disease modifiers","authors":"Holly J. Thorpe, Raghavendran Partha, Jordan Little, Nathan L. Clark, Clement Y. Chow","doi":"10.1371/journal.pgen.1011406","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011406","url":null,"abstract":"Mutations in glycosylation pathways, such as N-linked glycosylation, O-linked glycosylation, and GPI anchor synthesis, lead to Congenital Disorders of Glycosylation (CDG). CDG typically present with seizures, hypotonia, and developmental delay but display large clinical variability with symptoms affecting every system in the body. This variability suggests modifier genes might influence the phenotypes. Because of the similar physiology and clinical symptoms, there are likely common genetic modifiers between CDG. Here, we use evolution as a tool to identify common modifiers between CDG and glycosylation genes. Protein glycosylation is evolutionarily conserved from yeast to mammals. Evolutionary rate covariation (ERC) identifies proteins with similar evolutionary rates that indicate shared biological functions and pathways. Using ERC, we identified strong evolutionary rate signatures between proteins in the same and different glycosylation pathways. Genome-wide analysis of proteins showing significant ERC with GPI anchor synthesis proteins revealed strong signatures with ncRNA modification proteins and DNA repair proteins. We also identified strong patterns of ERC based on cellular sub-localization of the GPI anchor synthesis enzymes. Functional testing of the highest scoring candidates validated genetic interactions and identified novel genetic modifiers of CDG genes. ERC analysis of disease genes and biological pathways allows for rapid prioritization of potential genetic modifiers, which can provide a better understanding of disease pathophysiology and novel therapeutic targets.","PeriodicalId":20266,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2024-09-10DOI: 10.1371/journal.pgen.1011300
Hélène Gaillard, Toni Ciudad, Andrés Aguilera, Ralf E. Wellinger
{"title":"Histone variant H2A.Z is needed for efficient transcription-coupled NER and genome integrity in UV challenged yeast cells","authors":"Hélène Gaillard, Toni Ciudad, Andrés Aguilera, Ralf E. Wellinger","doi":"10.1371/journal.pgen.1011300","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011300","url":null,"abstract":"The genome of living cells is constantly challenged by DNA lesions that interfere with cellular processes such as transcription and replication. A manifold of mechanisms act in concert to ensure adequate DNA repair, gene expression, and genome stability. Bulky DNA lesions, such as those induced by UV light or the DNA-damaging agent 4-nitroquinoline oxide, act as transcriptional and replicational roadblocks and thus represent a major threat to cell metabolism. When located on the transcribed strand of active genes, these lesions are handled by transcription-coupled nucleotide excision repair (TC-NER), a yet incompletely understood NER sub-pathway. Here, using a genetic screen in the yeast <jats:italic>Saccharomyces cerevisiae</jats:italic>, we identified histone variant H2A.Z as an important component to safeguard transcription and DNA integrity following UV irradiation. In the absence of H2A.Z, repair by TC-NER is severely impaired and RNA polymerase II clearance reduced, leading to an increase in double-strand breaks. Thus, H2A.Z is needed for proficient TC-NER and plays a major role in the maintenance of genome stability upon UV irradiation.","PeriodicalId":20266,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The NF-κB Factor Relish maintains blood progenitor homeostasis in the developing Drosophila lymph gland","authors":"Parvathy Ramesh, Satish Kumar Tiwari, Md Kaizer, Deepak Jangra, Kaustuv Ghosh, Sudip Mandal, Lolitika Mandal","doi":"10.1371/journal.pgen.1011403","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011403","url":null,"abstract":"Post-larval hematopoiesis in <jats:italic>Drosophila</jats:italic> largely depends upon the stockpile of progenitors present in the blood-forming organ/lymph gland of the larvae. During larval stages, the lymph gland progenitors gradually accumulate reactive oxygen species (ROS), which is essential to prime them for differentiation. Studies have shown that ROS triggers the activation of JNK (c-Jun Kinase), which upregulates fatty acid oxidation (FAO) to facilitate progenitor differentiation. Intriguingly, despite having ROS, the entire progenitor pool does not differentiate simultaneously in the late larval stages. Using expression analyses, genetic manipulation and pharmacological approaches, we found that the <jats:italic>Drosophila</jats:italic> NF-κB transcription factor Relish (Rel) shields the progenitor pool from the metabolic pathway that inducts them into the differentiation program by curtailing the activation of JNK. Although ROS serves as the metabolic signal for progenitor differentiation, the input from ROS is monitored by the developmental signal TAK1, which is regulated by Relish. This developmental circuit ensures that the stockpile of ROS-primed progenitors is not exhausted entirely. Our study sheds light on how, during development, integrating NF-κB-like factors with metabolic pathways seem crucial to regulating cell fate transition during development.","PeriodicalId":20266,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2024-09-09DOI: 10.1371/journal.pgen.1011151
Nitin Kumar, Min-Lee Yang, Pengfei Sun, Kristina L. Hunker, Jianping Li, Jia Jia, Fangfang Fan, Jinghua Wang, Xianjia Ning, Wei Gao, Ming Xu, Jifeng Zhang, Lin Chang, Yuqing E. Chen, Yong Huo, Yan Zhang, Santhi K. Ganesh
{"title":"Genetic variation in CCDC93 is associated with elevated central systolic blood pressure, impaired arterial relaxation, and mitochondrial dysfunction","authors":"Nitin Kumar, Min-Lee Yang, Pengfei Sun, Kristina L. Hunker, Jianping Li, Jia Jia, Fangfang Fan, Jinghua Wang, Xianjia Ning, Wei Gao, Ming Xu, Jifeng Zhang, Lin Chang, Yuqing E. Chen, Yong Huo, Yan Zhang, Santhi K. Ganesh","doi":"10.1371/journal.pgen.1011151","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011151","url":null,"abstract":"Genetic studies of blood pressure (BP) traits to date have been performed on conventional measures by brachial cuff sphygmomanometer for systolic BP (SBP) and diastolic BP, integrating several physiologic occurrences. Genetic associations with central SBP (cSBP) have not been well-studied. Genetic discovery studies of BP have been most often performed in European-ancestry samples. Here, we investigated genetic associations with cSBP in a Chinese population and functionally validated the impact of a novel associated coiled-coil domain containing 93 (<jats:italic>CCDC93</jats:italic>) gene on BP regulation. An exome-wide association study (EWAS) was performed using a mixed linear model of non-invasive cSBP and peripheral BP traits in a Han Chinese population (N = 5,954) from Beijing, China genotyped with a customized Illumina ExomeChip array. We identified four SNP-trait associations with three SNPs, including two novel associations (rs2165468-SBP and rs33975708-cSBP). rs33975708 is a coding variant in the <jats:italic>CCDC93</jats:italic> gene, c.535C>T, p.Arg179Cys (MAF = 0.15%), and was associated with increased cSBP (β = 29.3 mmHg, <jats:italic>P</jats:italic> = 1.23x10<jats:sup>-7</jats:sup>). CRISPR/Cas9 genome editing was used to model the effect of <jats:italic>Ccdc93</jats:italic> loss in mice. Homozygous <jats:italic>Ccdc93</jats:italic> deletion was lethal prior to day 10.5 of embryonic development. <jats:italic>Ccdc93</jats:italic><jats:sup>+/-</jats:sup> heterozygous mice were viable and morphologically normal, with 1.3-fold lower aortic Ccdc93 protein expression (<jats:italic>P</jats:italic> = 0.0041) and elevated SBP as compared to littermate <jats:italic>Ccdc93</jats:italic><jats:sup>+/+</jats:sup> controls (110±8 mmHg vs 125±10 mmHg, <jats:italic>P</jats:italic> = 0.016). Wire myography of <jats:italic>Ccdc93</jats:italic><jats:sup>+/-</jats:sup> aortae showed impaired acetylcholine-induced relaxation and enhanced phenylephrine-induced contraction. RNA-Seq transcriptome analysis of <jats:italic>Ccdc93</jats:italic><jats:sup>+/-</jats:sup> mouse thoracic aortae identified significantly enriched pathways altered in fatty acid metabolism and mitochondrial metabolism. Plasma free fatty acid levels were elevated in <jats:italic>Ccdc93</jats:italic><jats:sup>+/-</jats:sup> mice (96±7mM vs 124±13mM, <jats:italic>P</jats:italic> = 0.0031) and aortic mitochondrial dysfunction was observed through aberrant Parkin and Nix protein expression. Together, our genetic and functional studies support a novel role of <jats:italic>CCDC93</jats:italic> in the regulation of BP through its effects on vascular mitochondrial function and endothelial function.","PeriodicalId":20266,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2023-09-18eCollection Date: 2023-09-01DOI: 10.1371/journal.pgen.1010546
Amanda Forde, Gibran Hemani, John Ferguson
{"title":"Review and further developments in statistical corrections for Winner's Curse in genetic association studies.","authors":"Amanda Forde, Gibran Hemani, John Ferguson","doi":"10.1371/journal.pgen.1010546","DOIUrl":"10.1371/journal.pgen.1010546","url":null,"abstract":"<p><p>Genome-wide association studies (GWAS) are commonly used to identify genomic variants that are associated with complex traits, and estimate the magnitude of this association for each variant. However, it has been widely observed that the association estimates of variants tend to be lower in a replication study than in the study that discovered those associations. A phenomenon known as Winner's Curse is responsible for this upward bias present in association estimates of significant variants in the discovery study. We review existing Winner's Curse correction methods which require only GWAS summary statistics in order to make adjustments. In addition, we propose modifications to improve existing methods and propose a novel approach which uses the parametric bootstrap. We evaluate and compare methods, first using a wide variety of simulated data sets and then, using real data sets for three different traits. The metric, estimated mean squared error (MSE) over significant SNPs, was primarily used for method assessment. Our results indicate that widely used conditional likelihood based methods tend to perform poorly. The other considered methods behave much more similarly, with our proposed bootstrap method demonstrating very competitive performance. To complement this review, we have developed an R package, 'winnerscurse' which can be used to implement these various Winner's Curse adjustment methods to GWAS summary statistics.</p>","PeriodicalId":20266,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2023-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10538662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10673009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2023-09-18eCollection Date: 2023-09-01DOI: 10.1371/journal.pgen.1010947
Calum A Graham, Pirita Paajanen, Keith J Edwards, Antony N Dodd
{"title":"Genome-wide circadian gating of a cold temperature response in bread wheat.","authors":"Calum A Graham, Pirita Paajanen, Keith J Edwards, Antony N Dodd","doi":"10.1371/journal.pgen.1010947","DOIUrl":"10.1371/journal.pgen.1010947","url":null,"abstract":"<p><p>Circadian rhythms coordinate the responses of organisms with their daily fluctuating environments, by establishing a temporal program of gene expression. This schedules aspects of metabolism, physiology, development and behaviour according to the time of day. Circadian regulation in plants is extremely pervasive, and is important because it underpins both productivity and seasonal reproduction. Circadian regulation extends to the control of environmental responses through a regulatory process known as circadian gating. Circadian gating is the process whereby the circadian clock regulates the response to an environmental cue, such that the magnitude of response to an identical cue varies according to the time of day of the cue. Here, we show that there is genome-wide circadian gating of responses to cold temperatures in plants. By using bread wheat as an experimental model, we establish that circadian gating is crucial to the programs of gene expression that underlie the environmental responses of a crop of major socioeconomic importance. Furthermore, we identify that circadian gating of cold temperature responses are distributed unevenly across the three wheat subgenomes, which might reflect the geographical origins of the ancestors of modern wheat.</p>","PeriodicalId":20266,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2023-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10538658/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10307575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2023-09-18eCollection Date: 2023-09-01DOI: 10.1371/journal.pgen.1010944
Susanna K Birnbaum, Jennifer D Cohen, Alexandra Belfi, John I Murray, Jennifer R G Adams, Andrew D Chisholm, Meera V Sundaram
{"title":"The proprotein convertase BLI-4 promotes collagen secretion prior to assembly of the Caenorhabditis elegans cuticle.","authors":"Susanna K Birnbaum, Jennifer D Cohen, Alexandra Belfi, John I Murray, Jennifer R G Adams, Andrew D Chisholm, Meera V Sundaram","doi":"10.1371/journal.pgen.1010944","DOIUrl":"10.1371/journal.pgen.1010944","url":null,"abstract":"<p><p>Some types of collagens, including transmembrane MACIT collagens and C. elegans cuticle collagens, are N-terminally cleaved at a dibasic site that resembles the consensus for furin or other proprotein convertases of the subtilisin/kexin (PCSK) family. Such cleavage may release transmembrane collagens from the plasma membrane and affect extracellular matrix assembly or structure. However, the functional consequences of such cleavage are unclear and evidence for the role of specific PCSKs is lacking. Here, we used endogenous collagen fusions to fluorescent proteins to visualize the secretion and assembly of the first collagen-based cuticle in C. elegans and then tested the role of the PCSK BLI-4 in these processes. Unexpectedly, we found that cuticle collagens SQT-3 and DPY-17 are secreted into the extraembryonic space several hours before cuticle matrix assembly. Furthermore, this early secretion depends on BLI-4/PCSK; in bli-4 and cleavage-site mutants, SQT-3 and DPY-17 are not efficiently secreted and instead form large intracellular puncta. Their later assembly into cuticle matrix is reduced but not entirely blocked. These data reveal a role for collagen N-terminal processing in intracellular trafficking and the control of matrix assembly in vivo. Our observations also prompt a revision of the classic model for C. elegans cuticle matrix assembly and the pre-cuticle-to-cuticle transition, suggesting that cuticle layer assembly proceeds via a series of regulated steps and not simply by sequential secretion and deposition.</p>","PeriodicalId":20266,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2023-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10538796/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10360972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}