So Who Kang, Jung-Eun Park, Soonhyuck Ok, Minhui Um, Hyeonjeong Son, Seunghee Byun, Nayoung Park, Su Jin Lee, Thị Xuân Thùy Trần, Gyeongmin Kim, Jeonghun Yeom, Kyunggon Kim, Eun Young Kim, Min-Ji Kang
{"title":"Drosophila ubiquitin-specific peptidase 14 stabilizes the PERIOD protein by regulating a ubiquitin ligase SLIMB.","authors":"So Who Kang, Jung-Eun Park, Soonhyuck Ok, Minhui Um, Hyeonjeong Son, Seunghee Byun, Nayoung Park, Su Jin Lee, Thị Xuân Thùy Trần, Gyeongmin Kim, Jeonghun Yeom, Kyunggon Kim, Eun Young Kim, Min-Ji Kang","doi":"10.1038/s42003-025-07632-9","DOIUrl":"https://doi.org/10.1038/s42003-025-07632-9","url":null,"abstract":"<p><p>The circadian clock orchestrates behavior and physiology through the oscillation of key clock proteins like PERIOD (PER). Here, we investigate the role of ubiquitin-specific peptidase 14 (USP14) in modulating PER stability and circadian rhythms in Drosophila. We find that overexpression of USP14 in clock cells reduces PER protein levels without altering its mRNA levels whereas USP14 knockdown increases PER protein levels, suggesting that USP14 regulates PER post-translationally. Interestingly, despite these alterations in PER levels, neither USP14 overexpression nor knockdown significantly impacts circadian behavioral rhythms, likely because of slight effects on PER levels in small ventral lateral neurons (sLN<sub>v</sub>s). Further analysis shows that USP14 physically interacts with Supernumerary Limbs (SLIMB), a protein involved in PER degradation. Moreover, reducing slimb expression mitigates the effects of USP14 on PER protein stability. Mass spectrometry identifies two ubiquitination sites on PER (Lys1117 and Lys1118) critical for its degradation. Expression of PER<sup>1117A, 1118A</sup> mutant in per<sup>01</sup> background impairs circadian rhythm strength. In conclusion, this study demonstrates that Drosophila USP14 indirectly modulates PER protein stability by affecting SLIMB and highlights the critical role of specific ubiquitination sites on PER in maintaining circadian rhythms.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"8 1","pages":"191"},"PeriodicalIF":5.2,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370553","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}
Jan Rynes, Eva Istvankova, Michaela Dzurov Krafcikova, Enrico Luchinat, Letizia Barbieri, Lucia Banci, Kristyna Kamarytova, Tomas Loja, Bohumil Fafilek, Gustavo Rico-Llanos, Pavel Krejci, Libor Macurek, Silvie Foldynova-Trantirkova, Lukas Trantirek
{"title":"Protein structure and interactions elucidated with in-cell NMR for different cell cycle phases and in 3D human tissue models.","authors":"Jan Rynes, Eva Istvankova, Michaela Dzurov Krafcikova, Enrico Luchinat, Letizia Barbieri, Lucia Banci, Kristyna Kamarytova, Tomas Loja, Bohumil Fafilek, Gustavo Rico-Llanos, Pavel Krejci, Libor Macurek, Silvie Foldynova-Trantirkova, Lukas Trantirek","doi":"10.1038/s42003-025-07607-w","DOIUrl":"https://doi.org/10.1038/s42003-025-07607-w","url":null,"abstract":"<p><p>Most of our knowledge of protein structure and function originates from experiments performed with purified proteins resuspended in dilute, buffered solutions. However, most proteins function in crowded intracellular environments with complex compositions. Significant efforts have been made to develop tools to study proteins in their native cellular settings. Among these tools, in-cell NMR spectroscopy has been the sole technique for characterizing proteins in the intracellular space of living cells at atomic resolution and physiological temperature. Nevertheless, due to technological constraints, in-cell NMR studies have been limited to asynchronous single-cell suspensions, precluding obtaining information on protein behavior in different cellular states. In this study, we present a methodology that allows for obtaining an atomically resolved NMR readout of protein structure and interactions in living human cells synchronized in specific cell cycle phases and within 3D models of human tissue. The described approach opens avenues for investigating how protein structure or drug recognition responds to cell-cell communication or changes in intracellular space composition during transitions among cell cycle phases.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"8 1","pages":"194"},"PeriodicalIF":5.2,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370529","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":"Simulating the impact of white matter connectivity on processing time scales using brain network models.","authors":"Paul Triebkorn, Viktor Jirsa, Peter Ford Dominey","doi":"10.1038/s42003-025-07587-x","DOIUrl":"https://doi.org/10.1038/s42003-025-07587-x","url":null,"abstract":"<p><p>The capacity of the brain to process input across temporal scales is exemplified in human narrative, which requires integration of information ranging from words, over sentences to long paragraphs. It has been shown that this processing is distributed in a hierarchy across multiple areas in the brain with areas close to the sensory cortex, processing on a faster time scale than areas in associative cortex. In this study we used reservoir computing with human derived connectivity to investigate the effect of the structural connectivity on time scales across brain regions during a narrative task paradigm. We systematically tested the effect of removal of selected fibre bundles (IFO, ILF, MLF, SLF I/II/III, UF, AF) on the processing time scales across brain regions. We show that long distance pathways such as the IFO provide a form of shortcut whereby input driven activation in the visual cortex can directly impact distant frontal areas. To validate our model we demonstrated significant correlation of our predicted time scale ordering with empirical results from the intact/scrambled narrative fMRI task paradigm. This study emphasizes structural connectivity's role in brain temporal processing hierarchies, providing a framework for future research on structure and neural dynamics across cognitive tasks.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"8 1","pages":"197"},"PeriodicalIF":5.2,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370533","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}
Justin Torok, Pedro D Maia, Chaitali Anand, Ashish Raj
{"title":"Searching for the cellular underpinnings of the selective vulnerability to tauopathic insults in Alzheimer's disease.","authors":"Justin Torok, Pedro D Maia, Chaitali Anand, Ashish Raj","doi":"10.1038/s42003-025-07575-1","DOIUrl":"10.1038/s42003-025-07575-1","url":null,"abstract":"<p><p>Neurodegenerative diseases such as Alzheimer's disease exhibit pathological changes in the brain that proceed in a stereotyped and regionally specific fashion. However, the cellular underpinnings of regional vulnerability are poorly understood, in part because whole-brain maps of a comprehensive collection of cell types have been inaccessible. Here, we deployed a recent cell-type mapping pipeline, Matrix Inversion and Subset Selection (MISS), to determine the brain-wide distributions of pan-hippocampal and neocortical cells in the mouse, and then used these maps to identify general principles of cell-type-based selective vulnerability in PS19 mouse models. We found that hippocampal glutamatergic neurons as a whole were significantly positively associated with regional tau deposition, suggesting vulnerability, while cortical glutamatergic and GABAergic neurons were negatively associated. We also identified oligodendrocytes as the single-most strongly negatively associated cell type. Further, cell-type distributions were more predictive of end-time-point tau pathology than AD-risk-gene expression. Using gene ontology analysis, we found that the genes that are directly correlated to tau pathology are functionally distinct from those that constitutively embody the vulnerable cells. In short, we have elucidated cell-type correlates of tau deposition across mouse models of tauopathy, advancing our understanding of selective cellular vulnerability at a whole-brain level.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"8 1","pages":"195"},"PeriodicalIF":5.2,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370530","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}
Jingtong Liu, Yao Wang, Jingjing Wei, Shengzhou Wang, Miaomiao Li, Zheyong Huang, Sufang Zhang, Huihui Liu, Jinhai Huang, Yongming Wang
{"title":"Enhanced genome editing with a Streptococcus equinus Cas9.","authors":"Jingtong Liu, Yao Wang, Jingjing Wei, Shengzhou Wang, Miaomiao Li, Zheyong Huang, Sufang Zhang, Huihui Liu, Jinhai Huang, Yongming Wang","doi":"10.1038/s42003-025-07593-z","DOIUrl":"https://doi.org/10.1038/s42003-025-07593-z","url":null,"abstract":"<p><p>A large number of SpCas9 orthologs has been computationally identified, but their genome editing potential remains largely unknown. In this study, a GFP-activation assay was used to screen a panel of 18 SpCas9 orthologs, ten of which demonstrated activity in human cells. Notably, these orthologs had a preference for purine-rich PAM sequences. Four of the tested orthologs displayed enhanced specificity compared to SpCas9. Of particular interest is SeqCas9, which recognizes a simple NNG PAM and displays activity and specificity comparable to SpCas9-HF1. In addition, SeqCas9 exhibits superior base editing efficiency compared to SpCas9-NG and SpCas9-NRRH at multiple endogenous loci. This research sheds light on the diversity of SpCas9 orthologs and their potential for specific and efficient genome editing, especially in cases involving base editing.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"8 1","pages":"196"},"PeriodicalIF":5.2,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370567","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}
Sreelakshmi K Sreenivasamurthy, Carlos Gustavo Baptista, Christopher M West, Ira J Blader, Jeffrey D Dvorin
{"title":"PfFBXO1 is essential for inner membrane complex formation in Plasmodium falciparum during both asexual and transmission stages.","authors":"Sreelakshmi K Sreenivasamurthy, Carlos Gustavo Baptista, Christopher M West, Ira J Blader, Jeffrey D Dvorin","doi":"10.1038/s42003-025-07619-6","DOIUrl":"10.1038/s42003-025-07619-6","url":null,"abstract":"<p><p>Plasmodium species replicate via schizogony, which involves asynchronous nuclear divisions followed by semi-synchronous segmentation and cytokinesis. Successful segmentation requires a double-membranous structure known as the inner membrane complex (IMC). Here we demonstrate that PfFBXO1 (PF3D7_0619700) is critical for both asexual segmentation and gametocyte maturation. In Toxoplasma gondii, the FBXO1 homolog, TgFBXO1, is essential for the development of the daughter cell scaffold and a component of the daughter cell IMC. We demonstrate PfFBXO1 forming a similar IMC initiation scaffold near the apical region of developing merozoites and unilaterally positioned in gametocytes of P. falciparum. While PfFBXO1 initially localizes to the apical region of dividing parasites, it displays an IMC-like localization as segmentation progresses. Similarly, PfFBXO1 localizes to the IMC region in gametocytes. Following inducible knockout of PfFBXO1, parasites undergo abnormal segmentation and karyokinesis, generating inviable daughters. PfFBXO1-deficient gametocytes are abnormally shaped and fail to fully mature. Proteomic analysis identified PfSKP1 as one of PfBXO1's stable interacting partners, while other major proteins included multiple IMC pellicle and membrane proteins. We hypothesize that PfFBXO1 is necessary for IMC biogenesis, chromosomal maintenance, vesicular transport, and ubiquitin-mediated translational regulation of proteins in both sexual and asexual stages of P. falciparum.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"8 1","pages":"190"},"PeriodicalIF":5.2,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364062","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}
Gloria Mavinga Bundutidi, Kota Mochizuki, Yuichi Matsuo, Mizuki Hayashishita, Takaya Sakura, Yuri Ando, Gregory Murray Cook, Acharjee Rajib, Frédéric Bringaud, Michael Boshart, Shinjiro Hamano, Masakazu Sekijima, Kenji Hirayama, Kiyoshi Kita, Daniel Ken Inaoka
{"title":"Development of tolerance to bedaquiline by overexpression of trypanosomal acetate: succinate CoA transferase in Mycobacterium smegmatis.","authors":"Gloria Mavinga Bundutidi, Kota Mochizuki, Yuichi Matsuo, Mizuki Hayashishita, Takaya Sakura, Yuri Ando, Gregory Murray Cook, Acharjee Rajib, Frédéric Bringaud, Michael Boshart, Shinjiro Hamano, Masakazu Sekijima, Kenji Hirayama, Kiyoshi Kita, Daniel Ken Inaoka","doi":"10.1038/s42003-025-07611-0","DOIUrl":"10.1038/s42003-025-07611-0","url":null,"abstract":"<p><p>The F-type ATP synthase inhibitor bedaquiline (BDQ) is a potent inhibitor of mycobacterial growth and this inhibition cannot be rescued by fermentable carbon sources that would supply ATP by an alternative pathway (substrate level phosphorylation). To gain mechanistic insight into this phenomenon, we employed a metabolic engineering approach. We introduced into Mycobacterium smegmatis an alternative ATP production pathway by substrate-level phosphorylation, specifically through overexpression of trypanosomal acetate:succinate co-enzyme A (CoA) transferase (ASCT). Intriguingly, the overexpression of ASCT partially restored intracellular ATP levels and resulted in acquired tolerance to BDQ growth inhibition at low, but not high concentrations of BDQ. These results implicate intracellular ATP levels in modulating the growth inhibitory activity of BDQ at low concentrations. These findings shed light on the intricate interplay between BDQ and mycobacterial energy metabolism, while also providing a novel tool for the development of next-generation ATP synthase-specific inhibitors targeting mycobacteria.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"8 1","pages":"187"},"PeriodicalIF":5.2,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363950","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}
Andrew Dang, Gary D Bernard, Furong Yuan, Aide Macias-Muñoz, Ryan I Hill, J P Lawrence, Aline Giselle Rangel Olguin, Armando Luis-Martínez, Sean P Mullen, Jorge Llorente-Bousquets, Adriana D Briscoe
{"title":"Trichromacy is insufficient for mate detection in a mimetic butterfly.","authors":"Andrew Dang, Gary D Bernard, Furong Yuan, Aide Macias-Muñoz, Ryan I Hill, J P Lawrence, Aline Giselle Rangel Olguin, Armando Luis-Martínez, Sean P Mullen, Jorge Llorente-Bousquets, Adriana D Briscoe","doi":"10.1038/s42003-025-07472-7","DOIUrl":"10.1038/s42003-025-07472-7","url":null,"abstract":"<p><p>Color vision is thought to play a key role in the evolution of animal coloration, while achromatic vision is rarely considered as a mechanism for species recognition. Here we test the hypothesis that brightness vision rather than color vision helps Adelpha fessonia butterflies identify potential mates while their co-mimetic wing coloration is indiscriminable to avian predators. We examine the trichromatic visual system of A. fessonia and characterize its photoreceptors using RNA-seq, eyeshine, epi-microspectrophotometry, and optophysiology. We model the discriminability of its wing color patches in relation to those of its co-mimic, A. basiloides, through A. fessonia and avian eyes. Visual modeling suggests that neither A. fessonia nor avian predators can readily distinguish the co-mimics' coloration using chromatic or achromatic vision under natural conditions. These results suggest that mimetic colors are well-matched to visual systems to maintain mimicry, and that mate avoidance between these two look-alike species relies on other cues.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"8 1","pages":"189"},"PeriodicalIF":5.2,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364117","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":"Expanding Yarrowia lipolytica's metabolic potential for detoxification of cyanogenic glycosides in edible plants.","authors":"Fidelis Azi, Zhiyu Li, Peng Xu","doi":"10.1038/s42003-025-07628-5","DOIUrl":"10.1038/s42003-025-07628-5","url":null,"abstract":"<p><p>Cyanides are highly toxic chemicals in several edible plants that threaten food safety and human health. A phenotypically distinct Yarrowia lipolytica strain that efficiently detoxifies multiple cyanogenic glycosides from edible plants was constructed using a family 1 glycosyl-hydrolase (GH1). The strain displayed higher growth rates and metabolic activities when exposed to high concentrations of cyanides than the wild-type. It overexpressed genes that promoted the binding of molecular oxygen to the cytochrome iv complex. The engineered strain repressed fatty acid production to optimize energy production and activated the cyanide-resistant respiratory (AOX) pathway to circumvent HCN toxicity and maintain cellular homeostasis. It upregulated ribosome biogenesis, the sec-dependent protein export pathway, and the sulfur relay system to facilitate the production and transmembrane efflux of the secreted GH1 hydrolase. It efficiently degraded linamarin, amygdalin, prunasin, and dhurrin in food plants including cassava, germinated sorghum and Apricot seeds. The strain produced high phospholipids to support new membrane production and could be a cost-effective source of single-cell phospholipids. The findings demonstrate that the strain is a robust, sustainable, and potentially efficient strain that could be used for industrial bioconversion of plant materials containing glycosylated toxicants into safe foods and animal feeds.</p>","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":"8 1","pages":"188"},"PeriodicalIF":5.2,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364055","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}