Proceedings of the National Academy of Sciences of the United States of America最新文献_第10页

Enforced CARD11/MALT1 signaling in dendritic cells triggers hemophagocytic lymphohistiocytosis.

IF 9.4 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2024-12-17 Epub Date: 2024-12-11 DOI: 10.1073/pnas.2413162121

Sophie E Isay, Larsen Vornholz, Theresa Schnalzger, Tanja Groll, Thomas Magg, Patricia Loll, Gregor Weirich, Katja Steiger, Fabian Hauck, Jürgen Ruland

{"title":"Enforced CARD11/MALT1 signaling in dendritic cells triggers hemophagocytic lymphohistiocytosis.","authors":"Sophie E Isay, Larsen Vornholz, Theresa Schnalzger, Tanja Groll, Thomas Magg, Patricia Loll, Gregor Weirich, Katja Steiger, Fabian Hauck, Jürgen Ruland","doi":"10.1073/pnas.2413162121","DOIUrl":"https://doi.org/10.1073/pnas.2413162121","url":null,"abstract":"Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome fueled by uncontrolled mononuclear phagocyte activity, yet the innate immune mechanisms driving HLH pathogenesis remain elusive. Germline gain-of-function (GOF) mutations in CARD11, a pivotal regulator of lymphocyte antigen receptor signaling, cause the lymphoproliferative disease B-cell expansion with NF-κB and T-cell anergy, which is frequently associated with HLH development. Given that CARD11 is physiologically expressed not only in lymphocytes but also in dendritic cells (DCs), we explored whether enforced CARD11 signaling in DCs contributes to immunopathology. We demonstrated that exclusive DC-intrinsic expression of CARD11-GOF in mice was sufficient to induce a lethal autoinflammatory syndrome that mimicked human HLH. Mechanistically, DC-intrinsic CARD11-GOF signaling triggered cell-autonomous inflammatory cytokine production via MALT1 paracaspase engagement. Genetic deletion of Malt1 in CARD11-GOF-expressing animals reversed the hyperinflammatory phenotype. These results highlight the significant role of enforced CARD11/MALT1 signaling in DCs as a contributor to HLH pathology and suggest potential therapeutic strategies for HLH treatment.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"121 51","pages":"e2413162121"},"PeriodicalIF":9.4,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Calcium signaling triggers early high humidity responses in Arabidopsis thaliana.

IF 9.4 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2024-12-17 Epub Date: 2024-12-11 DOI: 10.1073/pnas.2416270121

Saad Hussain, Hiraku Suda, Christine H Nguyen, Dawei Yan, Masatsugu Toyota, Keiko Yoshioka, Eiji Nambara

{"title":"Calcium signaling triggers early high humidity responses in Arabidopsis thaliana.","authors":"Saad Hussain, Hiraku Suda, Christine H Nguyen, Dawei Yan, Masatsugu Toyota, Keiko Yoshioka, Eiji Nambara","doi":"10.1073/pnas.2416270121","DOIUrl":"https://doi.org/10.1073/pnas.2416270121","url":null,"abstract":"Plants need to adapt to fluctuating atmospheric humidity and respond to both high and low humidity. Despite our substantial understanding of plant responses to low humidity, molecular mechanisms underlying the high humidity (HH) response are much less well understood. In this study, we investigated early responses to HH in Arabidopsis. Expression of CYP707A3, encoding an abscisic acid (ABA) 8'-hydroxylase, is induced by HH within 10 min, which leads to a decrease in foliar ABA level. We identified that the combined action of CAMTA3 and CAMTA2 transcription factors regulate this response. This regulation requires a calmodulin (CaM)-binding domain of CAMTA3. Transcriptomes of HH-regulated genes are enriched in those related to calcium signaling, including cyclic nucleotide-gated ion channels (CNGCs). Moreover, HH induces CNGC2- and CNGC4-mediated increases in cytosolic Ca2+ concentrations in leaves within a few minutes. We also found that CNGC2, CNGC4, and CAMTAs participate in HH-induced hyponastic movement of petioles. Taken together, our results indicate that CNGC2/CNGC4-Ca2+-CaM-CAMTA3/CAMTA2 acts as a primary regulatory module to trigger downstream HH responses.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"121 51","pages":"e2416270121"},"PeriodicalIF":9.4,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Emergent polar order in nonpolar mixtures with nonreciprocal interactions.

IF 9.4 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2024-12-17 Epub Date: 2024-12-12 DOI: 10.1073/pnas.2407705121

Giulia Pisegna, Suropriya Saha, Ramin Golestanian

{"title":"Emergent polar order in nonpolar mixtures with nonreciprocal interactions.","authors":"Giulia Pisegna, Suropriya Saha, Ramin Golestanian","doi":"10.1073/pnas.2407705121","DOIUrl":"https://doi.org/10.1073/pnas.2407705121","url":null,"abstract":"Phenomenological rules that govern the collective behavior of complex physical systems are powerful tools because they can make concrete predictions about their universality class based on generic considerations, such as symmetries, conservation laws, and dimensionality. While in most cases such considerations are manifestly ingrained in the constituents, novel phenomenology can emerge when composite units associated with emergent symmetries dominate the behavior of the system. We study a generic class of active matter systems with nonreciprocal interactions and demonstrate the existence of true long-range polar order in two dimensions and above, both at the linear level and by including all relevant nonlinearities in the Renormalization Group sense. We achieve this by uncovering a mapping of our scalar active mixture theory to the Toner-Tu theory of dry polar active matter by employing a suitably defined polar order parameter. We then demonstrate that the complete effective field theory-which includes all the soft modes and the relevant nonlinear terms-belongs to the (Burgers-) Kardar-Parisi-Zhang universality class. This classification allows us to prove the stability of the emergent polar long-range order in scalar nonreciprocal mixtures in two dimensions, and hence a conclusive violation of the Mermin-Wagner theorem.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"121 51","pages":"e2407705121"},"PeriodicalIF":9.4,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mutation-based mechanism and evolution of the potent multidrug efflux pump RE-CmeABC in Campylobacter. 弯曲杆菌中强效多药外排泵 RE-CmeABC 基于突变的机制和进化。

IF 9.4 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2024-12-17 Epub Date: 2024-11-27 DOI: 10.1073/pnas.2415823121

Lei Dai, Zuowei Wu, Orhan Sahin, Shaohua Zhao, Edward W Yu, Qijing Zhang

{"title":"Mutation-based mechanism and evolution of the potent multidrug efflux pump RE-CmeABC in Campylobacter.","authors":"Lei Dai, Zuowei Wu, Orhan Sahin, Shaohua Zhao, Edward W Yu, Qijing Zhang","doi":"10.1073/pnas.2415823121","DOIUrl":"https://doi.org/10.1073/pnas.2415823121","url":null,"abstract":"The resistance-nodulation-cell division (RND) superfamily of multidrug efflux systems are important players in mediating antibiotic resistance in gram-negative pathogens. Campylobacter jejuni, a major enteric pathogen, utilizes an RND-type transporter system, CmeABC, as the primary mechanism for extrusion of various antibiotics. Recently, a functionally potent variant of CmeABC (named RE-CmeABC) emerged in clinical Campylobacter isolates, conferring enhanced resistance to multiple antibiotic classes. Despite the clinical importance of RE-CmeABC, the molecular mechanisms for its functional gain and its evolutionary trajectory remain unknown. Here, we demonstrated that amino acid substitutions in RE-CmeB (inner membrane transporter), but not in RE-CmeA (periplasmic protein) and RE-CmeC (outer membrane protein), in conjunction with a nucleotide mutation in the promoter region of the efflux operon, are responsible for the functional gain of the multidrug efflux system. We also showed that RE-cmeABC is emerging globally and distributed in genetically diverse C. jejuni strains, suggesting its possible spread by horizontal gene transfer. Notably, many of RE-cmeABC harboring isolates were associated with the human host including strains from large disease outbreaks, indicating the clinical relevance and significance of RE-CmeABC. Evolutionary analysis indicated that RE-cmeB likely originated from Campylobacter coli, but its expansion mainly occurred in C. jejuni, possibly driven by antibiotic selection pressure. Additionally, RE-cmeB, but not RE-cmeA and RE-cmeC, experienced a selective sweep and was progressing to be fixed during evolution. Together, these results identify a mutation-based mechanism for functional gain in RE-CmeABC and reveal the key role of RE-CmeB in facilitating Campylobacter adaptation to antibiotic selection.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"121 51","pages":"e2415823121"},"PeriodicalIF":9.4,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Reply to Araújo: Good science requires focus.

IF 9.4 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2024-12-17 Epub Date: 2024-12-11 DOI: 10.1073/pnas.2420476121

Sarab S Sethi, Avery Bick, Ming-Yuan Chen, Renato Crouzeilles, Ben V Hillier, Jenna Lawson, Chia-Yun Lee, Shih-Hao Liu, Celso Henrique de Freitas Parruco, Carolyn M Rosten, Marius Somveille, Mao-Ning Tuanmu, Cristina Banks-Leite

引用次数: 0

Increased perfluorooctanoic acid accumulation facilitates the migration and invasion of lung cancer cells via remodeling cell mechanics.

IF 9.4 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2024-12-17 Epub Date: 2024-12-12 DOI: 10.1073/pnas.2408575121

Jie Mei, Jipeng Jiang, Zhao Li, Yue Pan, Ke Xu, Xinglong Gao, Jing Yuan, Lili Li, Yufei Wang, Liuxiang Wang, Ailin Zhao, Shasha Jiang, Xinlian Wang, Shaoqiong Yi, Shilin Li, Yueguang Xue, Yongfu Ma, Yang Liu, Yawei Wang, Juan Li, Chunying Chen, Ying Liu

{"title":"Increased perfluorooctanoic acid accumulation facilitates the migration and invasion of lung cancer cells via remodeling cell mechanics.","authors":"Jie Mei, Jipeng Jiang, Zhao Li, Yue Pan, Ke Xu, Xinglong Gao, Jing Yuan, Lili Li, Yufei Wang, Liuxiang Wang, Ailin Zhao, Shasha Jiang, Xinlian Wang, Shaoqiong Yi, Shilin Li, Yueguang Xue, Yongfu Ma, Yang Liu, Yawei Wang, Juan Li, Chunying Chen, Ying Liu","doi":"10.1073/pnas.2408575121","DOIUrl":"https://doi.org/10.1073/pnas.2408575121","url":null,"abstract":"Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are widely used in industrial and household products, raising serious concerns due to their environmental persistence and mobility. Epidemiological studies have reported potential carcinogenic risks of PFAS based on their widespread occurrence and population exposure. In this study, we observed that perfluorooctanoic acid (PFOA), a common PFAS, functions as a mechanical regulator in lung cancer cells. PFOA exposure reduces cell stiffness, thereby decreasing cell adhesion and enhancing immune evasion, ultimately exacerbating tumor metastasis. In various lung cancer models, more aggressive tumor metastases have been observed in the PFOA exposure group. Additionally, serum PFOA levels in patients with advanced lung adenocarcinoma were significantly higher than those in patients with early-stage disease. Mechanistically, the interaction between PFOA and transmembrane integrins in cancer cells triggers changes in cellular mechanical properties, leading to the reorganization of the cytoskeleton, and activation of the intracellular FAK-PI3K-Akt signaling pathway. Our findings demonstrate that in individuals with lung adenocarcinoma, PFOA can increase the risk of cancer metastasis even at daily exposure levels.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"121 51","pages":"e2408575121"},"PeriodicalIF":9.4,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Molecular basis of lipid and ligand regulation of prostaglandin receptor DP2.

IF 9.4 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2024-12-17 Epub Date: 2024-12-12 DOI: 10.1073/pnas.2403304121

Jiuyin Xu, Youwei Xu, Li Hou, Xinheng He, Yang Li, Jing Zhao, Xue Meng, James Jiqi Wang, Yanli Wu, Heng Zhang, Yunhai Li, Wen Hu, Qingning Yuan, Kai Wu, Xi Cheng, Yi Jiang, Yu Xia, H Eric Xu, Canrong Wu

{"title":"Molecular basis of lipid and ligand regulation of prostaglandin receptor DP2.","authors":"Jiuyin Xu, Youwei Xu, Li Hou, Xinheng He, Yang Li, Jing Zhao, Xue Meng, James Jiqi Wang, Yanli Wu, Heng Zhang, Yunhai Li, Wen Hu, Qingning Yuan, Kai Wu, Xi Cheng, Yi Jiang, Yu Xia, H Eric Xu, Canrong Wu","doi":"10.1073/pnas.2403304121","DOIUrl":"https://doi.org/10.1073/pnas.2403304121","url":null,"abstract":"Prostaglandin D2 receptor 2 (DP2) is an important anti-inflammatory and antiallergic drug target. While inactive DP2 structures are known, its activation mechanisms and biased signaling remain unclear. Here, we report cryo-EM structures of an apo DP2-Gi complex, a DP2-Gi complex bound to the endogenous ligand Prostaglandin D2 (PGD2), and a DP2-Gi complex bound to indomethacin, an arrestin-biased ligand, at resolutions of 2.5 Å, 2.8Å, and 2.3 Å, respectively. These structures reveal a distinct binding pose of PGD2 and indomethacin and provide key insights into receptor activation and transducer coupling. Combining the structural data with functional studies, we uncover the molecular basis for biased signaling of indomethacin toward β-arrestin over G proteins. Notably, a phospholipid binding site was identified at the DP2-G protein interface that modulates DP2-G protein interactions. Together, our functional and structural findings provide insights into DP2 activation, biased signaling, drug interactions, and lipid regulation, enabling rational design of safer antiallergy therapeutics targeting this key immune receptor.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"121 51","pages":"e2403304121"},"PeriodicalIF":9.4,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Ion permeation through a narrow cavity constriction in KCNQ1 channels: Mechanism and implications for pathogenic variants.

IF 9.4 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2024-12-17 Epub Date: 2024-12-13 DOI: 10.1073/pnas.2411182121

Liana Mkrtchyan, Harutyun Sahakyan, Jodene Eldstrom, Tatev Karapetyan, Astghik Abrahamyan, Karen Nazaryan, Jürgen R Schwarz, Matthias Kneussel, David Fedida, Vitya Vardanyan

{"title":"Ion permeation through a narrow cavity constriction in KCNQ1 channels: Mechanism and implications for pathogenic variants.","authors":"Liana Mkrtchyan, Harutyun Sahakyan, Jodene Eldstrom, Tatev Karapetyan, Astghik Abrahamyan, Karen Nazaryan, Jürgen R Schwarz, Matthias Kneussel, David Fedida, Vitya Vardanyan","doi":"10.1073/pnas.2411182121","DOIUrl":"10.1073/pnas.2411182121","url":null,"abstract":"KCNQ1 potassium channels play a pivotal role in the physiology and pathophysiology of several human excitable and epithelial tissues. The latest cryo-electron microscopy (cryo-EM) structures provide unique insights into channel function and pharmacology, opening avenues for different therapeutic strategies against human diseases associated with KCNQ1 mutations. However, these structures also raise fundamental questions about the mechanisms of ion permeation. Cryo-EM structures thought to represent the open state of the channel feature a cavity region not wide enough for accommodation of hydrated K+. To understand how K+ passes through the cavity constriction, we utilized microsecond-scale molecular dynamics (MD) simulations using the KCNQ1/KCNE3 cryo-EM structure, characterized mutants at the G345 residue situated at the narrowest point of the cavity, and recorded single channels. The findings indicate that ions become partially dehydrated at the constriction, which enables permeation. MD simulations demonstrate that the constriction can impede the flow of ions through the channel's pore, a finding that is corroborated by mutational screening and single-channel recordings. Reduced channel conductance is the key mechanism underlying reported pathological KCNQ1 mutations at or near the constriction site.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"121 51","pages":"e2411182121"},"PeriodicalIF":9.4,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Temperature-dependent fold-switching mechanism of the circadian clock protein KaiB.

IF 9.4 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2024-12-17 Epub Date: 2024-12-13 DOI: 10.1073/pnas.2412327121

Ning Zhang, Damini Sood, Spencer C Guo, Nanhao Chen, Adam Antoszewski, Tegan Marianchuk, Supratim Dey, Yunxian Xiao, Lu Hong, Xiangda Peng, Michael Baxa, Carrie Partch, Lee-Ping Wang, Tobin R Sosnick, Aaron R Dinner, Andy LiWang

{"title":"Temperature-dependent fold-switching mechanism of the circadian clock protein KaiB.","authors":"Ning Zhang, Damini Sood, Spencer C Guo, Nanhao Chen, Adam Antoszewski, Tegan Marianchuk, Supratim Dey, Yunxian Xiao, Lu Hong, Xiangda Peng, Michael Baxa, Carrie Partch, Lee-Ping Wang, Tobin R Sosnick, Aaron R Dinner, Andy LiWang","doi":"10.1073/pnas.2412327121","DOIUrl":"10.1073/pnas.2412327121","url":null,"abstract":"The oscillator of the cyanobacterial circadian clock relies on the ability of the KaiB protein to switch reversibly between a stable ground-state fold (gsKaiB) and an unstable fold-switched fold (fsKaiB). Rare fold-switching events by KaiB provide a critical delay in the negative feedback loop of this posttranslational oscillator. In this study, we experimentally and computationally investigate the temperature dependence of fold switching and its mechanism. We demonstrate that the stability of gsKaiB increases with temperature compared to fsKaiB and that the Q10 value for the gsKaiB → fsKaiB transition is nearly three times smaller than that for the reverse transition in a construct optimized for NMR studies. Simulations and native-state hydrogen-deuterium exchange NMR experiments suggest that fold switching can involve both partially and completely unfolded intermediates. The simulations predict that the transition state for fold switching coincides with isomerization of conserved prolines in the most rapidly exchanging region, and we confirm experimentally that proline isomerization is a rate-limiting step for fold switching. We explore the implications of our results for temperature compensation, a hallmark of circadian clocks, through a kinetic model.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"121 51","pages":"e2412327121"},"PeriodicalIF":9.4,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

E93 controls adult differentiation by repressing broad in Drosophila.

IF 9.4 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2024-12-17 Epub Date: 2024-12-13 DOI: 10.1073/pnas.2403162121

Josefa Cruz, Enric Ureña, Luis P Iñiguez, Manuel Irimia, Xavier Franch-Marro, David Martín

{"title":"E93 controls adult differentiation by repressing broad in Drosophila.","authors":"Josefa Cruz, Enric Ureña, Luis P Iñiguez, Manuel Irimia, Xavier Franch-Marro, David Martín","doi":"10.1073/pnas.2403162121","DOIUrl":"https://doi.org/10.1073/pnas.2403162121","url":null,"abstract":"In Drosophila melanogaster, successful development relies on the precise coordination of both spatial and temporal regulatory axes. The temporal axis governs stage-specific identity and developmental transitions through a number of genes, collectively forming the Metamorphic Gene Network. Among these, Ecdysone inducible protein 93F (E93) serves as the critical determinant for adult specification, but its mechanism of action remains unclear. Here, we found that, rather than acting mainly as an instructive signal, E93 promotes adult differentiation through the repression of the pupal specifier broad (br). In the absence of E93, sustained high levels of Br during the pupal stage strongly represses pupal-specific enhancers that are essential for the terminal differentiation of the wing. Notably, RNA-seq analysis confirmed that the majority of E93-dependent transcriptomic changes in pupal wings are primarily driven by br repression. In addition, we also show that Br represses the pupal-enhancers during the larval and prepupal stages preventing the premature implementation of the adult genetic program, and that it also dampens the activity of larval enhancers during the latter stages of larval development. This mechanism of action seems to be a derived feature acquired in Diptera, as in the coleopteran Tribolium castaneum, repression of br by E93 is not sufficient to allow adult differentiation. In summary, our study elucidates the crucial role of the intricate interplay between E93 and Br as the governing mechanism in the process of terminal differentiation in Drosophila. This finding holds significant implications for advancing our understanding of the evolution of insect metamorphosis.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"121 51","pages":"e2403162121"},"PeriodicalIF":9.4,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0