Cell reportsPub Date : 2025-01-28Epub Date: 2025-01-15DOI: 10.1016/j.celrep.2024.115213
Robert S Porter, Sojin An, Maria C Gavilan, Masayoshi Nagai, Yumie Murata-Nakamura, Bo Zhou, Katherine M Bonefas, Olivier Dionne, Jeru Manoj Manuel, Joannie St-Germain, Suzanne Gascon, Jacqueline Kim, Liam Browning, Benoit Laurent, Uhn-Soo Cho, Shigeki Iwase
{"title":"Coordinated neuron-specific splicing events restrict nucleosome engagement of the LSD1 histone demethylase complex.","authors":"Robert S Porter, Sojin An, Maria C Gavilan, Masayoshi Nagai, Yumie Murata-Nakamura, Bo Zhou, Katherine M Bonefas, Olivier Dionne, Jeru Manoj Manuel, Joannie St-Germain, Suzanne Gascon, Jacqueline Kim, Liam Browning, Benoit Laurent, Uhn-Soo Cho, Shigeki Iwase","doi":"10.1016/j.celrep.2024.115213","DOIUrl":"10.1016/j.celrep.2024.115213","url":null,"abstract":"<p><p>Chromatin regulatory proteins are expressed broadly and assumed to exert the same intrinsic function across cell types. Here, we report that 14 chromatin regulators undergo evolutionary-conserved neuron-specific splicing events involving microexons. Among them are two components of a histone demethylase complex: LSD1 H3K4 demethylase and the H3K4me0-reader PHF21A. We found that neuronal LSD1 splicing reduces the enzymes' affinity to the nucleosome. Meanwhile, neuronal PHF21A splicing significantly attenuates histone H3 binding and further ablates the DNA-binding function exerted by an AT-hook motif. Furthermore, in vitro reconstitution of the canonical and neuronal PHF21A-LSD1 complexes, combined with in vivo methylation mapping, identified the neuronal complex as a hypomorphic H3K4 demethylating machinery. The neuronal PHF21A, albeit with its weaker nucleosome binding, is necessary for normal gene expression and the H3K4 landscape in the developing brain. Thus, ubiquitously expressed chromatin regulatory complexes can exert neuron-specific functions via alternative splicing of their subunits.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115213"},"PeriodicalIF":7.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000708","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}
Cell reportsPub Date : 2025-01-28Epub Date: 2025-01-15DOI: 10.1016/j.celrep.2024.115194
Ashleigh Willis, Danielle Jeong, Yunlong Liu, Marissa A Lithopoulos, Scott A Yuzwa, Paul W Frankland, David R Kaplan, Freda D Miller
{"title":"Single cell approaches define neural stem cell niches and identify microglial ligands that can enhance precursor-mediated oligodendrogenesis.","authors":"Ashleigh Willis, Danielle Jeong, Yunlong Liu, Marissa A Lithopoulos, Scott A Yuzwa, Paul W Frankland, David R Kaplan, Freda D Miller","doi":"10.1016/j.celrep.2024.115194","DOIUrl":"10.1016/j.celrep.2024.115194","url":null,"abstract":"<p><p>Here, we used single cell RNA sequencing and single cell spatial transcriptomics to characterize the forebrain neural stem cell (NSC) niche under homeostatic and injury conditions. We defined the dorsal and lateral ventricular-subventricular zones (V-SVZs) as two distinct neighborhoods and showed that, after white matter injury, NSCs are activated to make oligodendrocytes dorsally for remyelination. This activation is coincident with an increase in transcriptionally distinct microglia in the dorsal V-SVZ niche. We modeled ligand-receptor interactions within this changing niche and identified two remyelination-associated microglial ligands, insulin growth factor 1 and oncostatin M, that promote precursor proliferation and oligodendrogenesis in culture. Infusion of either ligand into the lateral ventricles also enhanced oligodendrogenesis, even in the lateral V-SVZ, where NSCs normally make neuroblasts. These data support a model where gliogenesis versus neurogenesis is determined by the local NSC neighborhood and where injury-induced niche alterations promote NSC activation, local oligodendrogenesis, and likely contribute to myelin repair.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115194"},"PeriodicalIF":7.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000833","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}
Cell reportsPub Date : 2025-01-28Epub Date: 2025-01-17DOI: 10.1016/j.celrep.2024.115214
Ning Zhou, Jingchen Yu, Xujiao Liu, Chengxi Li, Huang Tang, Lin Lyu, Chengwei Wu, Yana Chen, Jian Zhang, Jinjing Ni, Danni Wang, Jing Tao, Wenjuan Wu, Yu Zhang, Yun Feng, Yanjie Chao, Jie Lu, Ping He, Yu-Feng Yao
{"title":"Within-host evolution of a transcriptional regulator contributes to the establishment of chronic Pseudomonas aeruginosa infection.","authors":"Ning Zhou, Jingchen Yu, Xujiao Liu, Chengxi Li, Huang Tang, Lin Lyu, Chengwei Wu, Yana Chen, Jian Zhang, Jinjing Ni, Danni Wang, Jing Tao, Wenjuan Wu, Yu Zhang, Yun Feng, Yanjie Chao, Jie Lu, Ping He, Yu-Feng Yao","doi":"10.1016/j.celrep.2024.115214","DOIUrl":"10.1016/j.celrep.2024.115214","url":null,"abstract":"<p><p>As an opportunistic pathogen, Pseudomonas aeruginosa can cause both acute and chronic infections that are notoriously difficult to treat. However, the mechanism underlying acute or chronic P. aeruginosa infection remains unclear. Here, we identify a mutation in a transcriptional regulator PA5438 (named GavR). This mutation causes a 3-amino-acid absence in GavR and is strongly associated with chronic P. aeruginosa infection. Mechanistically, the deletion in GavR directly downregulates the transcription of the aceEF operon and leads to an accumulation of intracellular pyruvate, which can promote bacterial survival in neutrophils. Notably, P. aeruginosa with 9-bp-deleted or full-length gavR composes a mixed population in most patients with chronic or acute infections. Overall, the mutation in gavR attenuates P. aeruginosa virulence and enhances innate immune evasion by reprogramming pyruvate metabolism and the glyoxylate cycle. This work reveals a molecular mechanism of transition control from acute to chronic infection in P. aeruginosa.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115214"},"PeriodicalIF":7.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000837","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}
Cell reportsPub Date : 2025-01-28Epub Date: 2025-01-14DOI: 10.1016/j.celrep.2024.115205
Mari Aikio, Hana M Odeh, Heike J Wobst, Bo Lim Lee, Úna Chan, Jocelyn C Mauna, Korrie L Mack, Bradley Class, Thomas A Ollerhead, Alice F Ford, Edward M Barbieri, Ryan R Cupo, Lauren E Drake, Joshua L Smalley, Yuan-Ta Lin, Stephanie Lam, Reuben Thomas, Nicholas Castello, Ashmita Baral, Jenna N Beyer, Mohd A Najar, John Dunlop, Aaron D Gitler, Ashkan Javaherian, Julia A Kaye, George M Burslem, Dean G Brown, Christopher J Donnelly, Steven Finkbeiner, Stephen J Moss, Nicholas J Brandon, James Shorter
{"title":"Opposing roles of p38α-mediated phosphorylation and PRMT1-mediated arginine methylation in driving TDP-43 proteinopathy.","authors":"Mari Aikio, Hana M Odeh, Heike J Wobst, Bo Lim Lee, Úna Chan, Jocelyn C Mauna, Korrie L Mack, Bradley Class, Thomas A Ollerhead, Alice F Ford, Edward M Barbieri, Ryan R Cupo, Lauren E Drake, Joshua L Smalley, Yuan-Ta Lin, Stephanie Lam, Reuben Thomas, Nicholas Castello, Ashmita Baral, Jenna N Beyer, Mohd A Najar, John Dunlop, Aaron D Gitler, Ashkan Javaherian, Julia A Kaye, George M Burslem, Dean G Brown, Christopher J Donnelly, Steven Finkbeiner, Stephen J Moss, Nicholas J Brandon, James Shorter","doi":"10.1016/j.celrep.2024.115205","DOIUrl":"10.1016/j.celrep.2024.115205","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder typically characterized by insoluble inclusions of hyperphosphorylated TDP-43. The mechanisms underlying toxic TDP-43 accumulation are not understood. Persistent activation of p38 mitogen-activated protein kinase (MAPK) is implicated in ALS. However, it is unclear how p38 MAPK affects TDP-43 proteinopathy. Here, we show that p38α MAPK inhibition reduces pathological TDP-43 phosphorylation, aggregation, cytoplasmic mislocalization, and neurotoxicity. Remarkably, p38α MAPK inhibition mitigates aberrant TDP-43 phenotypes in diverse ALS patient-derived motor neurons. p38α MAPK phosphorylates TDP-43 at pathological S409/S410 and S292, which reduces TDP-43 liquid-liquid phase separation (LLPS) but allows pathological TDP-43 aggregation. Moreover, we establish that PRMT1 methylates TDP-43 at R293. Importantly, S292 phosphorylation reduces R293 methylation, and R293 methylation reduces S409/S410 phosphorylation. Notably, R293 methylation permits TDP-43 LLPS and reduces pathological TDP-43 aggregation. Thus, strategies to reduce p38α-mediated TDP-43 phosphorylation and promote PRMT1-mediated R293 methylation could have therapeutic utility for ALS and related TDP-43 proteinopathies.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115205"},"PeriodicalIF":7.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000808","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}
Cell reportsPub Date : 2025-01-28Epub Date: 2025-01-10DOI: 10.1016/j.celrep.2024.115202
Ashley F George, Jason Neidleman, Xiaoyu Luo, Julie Frouard, Natalie Elphick, Kailin Yin, Kyrlia C Young, Tongcui Ma, Alicer K Andrew, Ifeanyi J Ezeonwumelu, Jesper G Pedersen, Antoine Chaillon, Magali Porrachia, Brendon Woodworth, Martin R Jakobsen, Reuben Thomas, Davey M Smith, Sara Gianella, Nadia R Roan
{"title":"Anatomical, subset, and HIV-dependent expression of viral sensors and restriction factors.","authors":"Ashley F George, Jason Neidleman, Xiaoyu Luo, Julie Frouard, Natalie Elphick, Kailin Yin, Kyrlia C Young, Tongcui Ma, Alicer K Andrew, Ifeanyi J Ezeonwumelu, Jesper G Pedersen, Antoine Chaillon, Magali Porrachia, Brendon Woodworth, Martin R Jakobsen, Reuben Thomas, Davey M Smith, Sara Gianella, Nadia R Roan","doi":"10.1016/j.celrep.2024.115202","DOIUrl":"10.1016/j.celrep.2024.115202","url":null,"abstract":"<p><p>We developed viral sensor and restriction factor-cytometry by time of flight (VISOR-CyTOF), which profiles 19 viral sensors and restriction factors (VISORs) simultaneously in single cells, and applied it to 41 postmortem tissues from people with HIV. Mucosal myeloid cells are well equipped with SAMHD1 and sensors of viral capsid and DNA while CD4<sup>+</sup> T cells are not. In lymph node CD4<sup>+</sup> Tfh, VISOR expression patterns reflect those favoring integration but blocking HIV gene expression, thus favoring viral latency. We also identify small subsets of bone marrow-, lung-, and gut-associated CD4<sup>+</sup> T and myeloid cells expressing high levels of restriction factors targeting most stages of the HIV replication cycle. In vitro, HIV preferentially fuses to CD4<sup>+</sup> T cells with a permissive VISOR profile, but early induction of select VISORs by T1IFN prevents productive HIV infection. Our findings document the diverse patterns of VISOR profiles across tissues and cellular subsets and define their association with susceptibility to HIV.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115202"},"PeriodicalIF":7.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969708","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}
Cell reportsPub Date : 2025-01-28Epub Date: 2024-12-26DOI: 10.1016/j.celrep.2024.115114
Benura Azeroglu, Simran Khurana, Shih-Chun Wang, Gianna M Tricola, Shalu Sharma, Camille Jubelin, Ylenia Cortolezzis, Gianluca Pegoraro, Kyle M Miller, Travis H Stracker, Eros Lazzerini Denchi
{"title":"Identification of modulators of the ALT pathway through a native FISH-based optical screen.","authors":"Benura Azeroglu, Simran Khurana, Shih-Chun Wang, Gianna M Tricola, Shalu Sharma, Camille Jubelin, Ylenia Cortolezzis, Gianluca Pegoraro, Kyle M Miller, Travis H Stracker, Eros Lazzerini Denchi","doi":"10.1016/j.celrep.2024.115114","DOIUrl":"10.1016/j.celrep.2024.115114","url":null,"abstract":"<p><p>A significant portion of human cancers utilize a recombination-based pathway, alternative lengthening of telomeres (ALT), to extend telomeres. To gain further insights into this pathway, we developed a high-throughput imaging-based screen named TAILS (telomeric ALT in situ localization screen) to identify genes that either promote or inhibit ALT activity. Screening over 1,000 genes implicated in DNA transactions, TAILS reveals both well-established and putative ALT modulators. Here, we present the validation of factors that promote ALT, such as the nucleosome-remodeling factor CHD4 and the chromatin reader SGF29, as well as factors that suppress ALT, including the RNA helicases DExD-box helicase 39A/B (DDX39A/B), the replication factor TIMELESS, and components of the chromatin assembly factor CAF1. Our data indicate that defects in histone deposition significantly contribute to ALT-associated phenotypes. Based on these findings, we demonstrate that pharmacological treatments can be employed to either exacerbate or suppress ALT-associated phenotypes.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115114"},"PeriodicalIF":7.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892539","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}
Cell reportsPub Date : 2025-01-28Epub Date: 2024-12-20DOI: 10.1016/j.celrep.2024.115031
Rokeya Sultana Rekha, Avinash Padhi, Nicolai Frengen, Julia Hauenstein, Ákos Végvári, Birgitta Agerberth, Robert Månsson, Guðmundur H Guðmundsson, Peter Bergman
{"title":"The di-leucine motif in the host defense peptide LL-37 is essential for initiation of autophagy in human macrophages.","authors":"Rokeya Sultana Rekha, Avinash Padhi, Nicolai Frengen, Julia Hauenstein, Ákos Végvári, Birgitta Agerberth, Robert Månsson, Guðmundur H Guðmundsson, Peter Bergman","doi":"10.1016/j.celrep.2024.115031","DOIUrl":"10.1016/j.celrep.2024.115031","url":null,"abstract":"<p><p>The human cathelicidin peptide LL-37 induces autophagy in human macrophages. Different post-translational modifications (PTMs) such as citrullination, acetylation, and formylation impact LL-37, yet their effect on autophagy remains unknown. Thus, we set out to study how the cellular source could impact PTM of LL-37 and subsequent effects on autophagy initiation. Neutrophil-released LL-37 failed to induce autophagy, unlike macrophage-released LL-37. Mass spectrometry analysis revealed modifications on neutrophil-derived LL-37, especially at the N terminus, while macrophage-derived LL-37 remained mostly native. Native LL-37 initiated autophagy, while formylated and acetylated versions did not. Truncated peptides lacking the N-terminal di-leucine motif or substituted with di-alanine did not initiate autophagy. Native LL-37 failed to initiate autophagy in macrophages with genetic inactivation of dipeptidyl peptidase-1. An intact N-terminal di-leucine motif in LL-37 was crucial for autophagy initiation, and modifications abrogated the effects. This pathway presents a novel way to regulate the effects of LL-37 in infection or inflammation.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115031"},"PeriodicalIF":7.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871522","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}
Cell reportsPub Date : 2025-01-28Epub Date: 2024-12-21DOI: 10.1016/j.celrep.2024.115107
Sebastian Held, Christian Erck, Susanna Kemppainen, Florian Bleibaum, Neha Jadhav Giridhar, Regina Feederle, Claudia Krenner, Sini-Pauliina Juopperi, Anna Calliari, Torben Mentrup, Bernd Schröder, Dennis W Dickson, Tuomas Rauramaa, Leonard Petrucelli, Mercedes Prudencio, Mikko Hiltunen, Patrick Lüningschrör, Anja Capell, Markus Damme
{"title":"Physiological shedding and C-terminal proteolytic processing of TMEM106B.","authors":"Sebastian Held, Christian Erck, Susanna Kemppainen, Florian Bleibaum, Neha Jadhav Giridhar, Regina Feederle, Claudia Krenner, Sini-Pauliina Juopperi, Anna Calliari, Torben Mentrup, Bernd Schröder, Dennis W Dickson, Tuomas Rauramaa, Leonard Petrucelli, Mercedes Prudencio, Mikko Hiltunen, Patrick Lüningschrör, Anja Capell, Markus Damme","doi":"10.1016/j.celrep.2024.115107","DOIUrl":"10.1016/j.celrep.2024.115107","url":null,"abstract":"<p><p>Genetic variants in TMEM106B, coding for a transmembrane protein of unknown function, have been identified as critical genetic modulators in various neurodegenerative diseases with a strong effect in patients with frontotemporal degeneration. The luminal domain of TMEM106B can form amyloid-like fibrils upon proteolysis. Whether this luminal domain is generated under physiological conditions and which protease(s) are involved in shedding remain unclear. We developed a commercially available antibody against the luminal domain of TMEM106B, allowing a detailed survey of the proteolytic processing under physiological conditions in cellular models and TMEM106B-related mouse models. Moreover, fibrillary TMEM106B was detected in human autopsy material. We find that the luminal domain is generated by multiple lysosomal cysteine-type proteases. Cysteine-type proteases perform additional C-terminal trimming, for which experimental evidence has been lacking. The presented results allow an in-depth perception of the processing of TMEM106B, a prerequisite to understanding factors leading to fibril formation.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115107"},"PeriodicalIF":7.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876340","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}
Cell reportsPub Date : 2025-01-28Epub Date: 2024-12-21DOI: 10.1016/j.celrep.2024.115084
Lele Cui, Shunhang Tang, Jingwei Pan, Li Deng, Zhaoran Zhang, Kai Zhao, Bailu Si, Ning-Long Xu
{"title":"Causal contributions of cell-type-specific circuits in the posterior dorsal striatum to auditory decision-making.","authors":"Lele Cui, Shunhang Tang, Jingwei Pan, Li Deng, Zhaoran Zhang, Kai Zhao, Bailu Si, Ning-Long Xu","doi":"10.1016/j.celrep.2024.115084","DOIUrl":"10.1016/j.celrep.2024.115084","url":null,"abstract":"<p><p>In the dorsal striatum (DS), the direct- and indirect-pathway striatal projection neurons (dSPNs and iSPNs) play crucial opposing roles in controlling actions. However, it remains unclear whether and how dSPNs and iSPNs provide distinct and specific contributions to decision-making, a process transforming sensory inputs to actions. Here, we perform causal interrogations on the roles of dSPNs and iSPNs in the posterior DS (pDS) in auditory-guided decision-making. Unilateral activation of dSPNs or iSPNs produces strong opposite drives to choice behaviors regardless of task difficulty. However, inactivation of dSPNs or iSPNs leads to pronounced choice bias preferentially in difficult trials, suggesting decision-specific contributions. Indeed, temporally specific iSPN activation within, but not outside, the decision period significantly biased choices. Finally, concurrent disinhibition of both pathways via inactivating parvalbumin (PV)-positive interneurons leads to contralateral bias primarily in difficult trials. These results reveal specific contributions by coordinated dSPN and iSPN activity to decision-making processes.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115084"},"PeriodicalIF":7.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876327","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}
Cell reportsPub Date : 2025-01-28Epub Date: 2024-12-20DOI: 10.1016/j.celrep.2024.115079
Wendy Figueroa, Adrian Cazares, Eleri A Ashworth, Aaron Weimann, Aras Kadioglu, R Andres Floto, Martin Welch
{"title":"Mutations in mexT bypass the stringent response dependency of virulence in Pseudomonas aeruginosa.","authors":"Wendy Figueroa, Adrian Cazares, Eleri A Ashworth, Aaron Weimann, Aras Kadioglu, R Andres Floto, Martin Welch","doi":"10.1016/j.celrep.2024.115079","DOIUrl":"10.1016/j.celrep.2024.115079","url":null,"abstract":"<p><p>Pseudomonas aeruginosa produces a wealth of virulence factors whose production is controlled via an intricate regulatory systems network. Here, we uncover a major player in the evolution and regulation of virulence that enhances host colonization and antibiotic resistance. By characterizing a collection of mutants lacking the stringent response (SR), a system key for virulence, we show that the loss of the central regulator MexT bypasses absence of the SR, restoring full activation of virulence pathways. Notably, mexT mutations were associated with resistance to aminoglycosides and the last-resort antibiotic, colistin. Analysis of thousands of P. aeruginosa genomes revealed that mexT mutations are widespread in isolates linked to aggressive antibiotic treatment. Furthermore, in vivo experiments in a murine pulmonary model revealed that mexT mutants display a hypervirulent phenotype associated with bacteremia. Altogether, these findings uncover a key regulator that acts as a genetic switch in the regulation of virulence and antimicrobial resistance.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115079"},"PeriodicalIF":7.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871517","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}
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