FEBS LettersPub Date : 2025-04-18DOI: 10.1002/1873-3468.70044
Foteini Karapanagioti, Sebastian Obermaier, Dirk J. Slotboom, Bert Poolman
{"title":"The Saccharomyces cerevisiae amino acid transporter Lyp1 has a broad substrate spectrum","authors":"Foteini Karapanagioti, Sebastian Obermaier, Dirk J. Slotboom, Bert Poolman","doi":"10.1002/1873-3468.70044","DOIUrl":"10.1002/1873-3468.70044","url":null,"abstract":"<p>The main mediators for the amino acid uptake in <i>Saccharomyces cerevisiae</i> are the permeases belonging to the yeast amino acid transporter family. Recently, we discovered that members of this family support growth on more amino acids than previously described. Here we study the substrate spectrum of Lyp1, the main transporter responsible for the uptake of lysine in yeast. We show that overexpressed Lyp1 supports growth on alanine, asparagine, leucine, methionine, phenylalanine, serine, and valine when these are provided as the sole source of nitrogen to a strain severely deficient for the uptake of amino acids. We show that alanine and serine compete with lysine for the common transport system, albeit with much lower affinity. Thus, Lyp1 has a much broader substrate spectrum than previously thought, which may be true for many amino acid transporters.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":"599 11","pages":"1609-1621"},"PeriodicalIF":3.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/1873-3468.70044","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143989128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS LettersPub Date : 2025-04-17DOI: 10.1002/1873-3468.70045
Abhishek Pethe, Tanja Nicole Hartmann
{"title":"The cytoskeletal control of B cell receptor and integrin signaling in normal B cells and chronic lymphocytic leukemia.","authors":"Abhishek Pethe, Tanja Nicole Hartmann","doi":"10.1002/1873-3468.70045","DOIUrl":"https://doi.org/10.1002/1873-3468.70045","url":null,"abstract":"<p><p>B cells migrate within lymphoid organs during maturation and activation, processes orchestrated by the interplay between B cell receptor (BCR) signaling and microenvironmental cues. Integrins act as mechanoreceptors, linking BCR activation to cytoskeletal remodeling, facilitating immune synapse formation, antigen recognition, and extraction. BCR activation models describe receptor clustering and mechanical changes within the antigen-BCR complex. Upon activation, immune synapses form, enabling antigen extraction and downstream signaling. Integrins stabilize these synapses, amplify BCR signaling, and modulate BCR positioning via actin reorganization. In chronic lymphocytic leukemia (CLL), aberrant BCR signaling and integrins are major players in leukemic cell homing, prognosis, and therapy resistance. In this review, we summarize the current understanding of the interplay of BCR mechanics and B cell localization, with a particular focus on communication between BCR signaling and integrin-mediated processes via actin dynamics. We give insights into normal B cell biology and then outline aspects typical to CLL.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143998526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS LettersPub Date : 2025-04-11DOI: 10.1002/1873-3468.70039
Stefania Oliveto, Nicola Manfrini, Stefano Biffo
{"title":"The power of microRNA regulation—insights into immunity and metabolism","authors":"Stefania Oliveto, Nicola Manfrini, Stefano Biffo","doi":"10.1002/1873-3468.70039","DOIUrl":"10.1002/1873-3468.70039","url":null,"abstract":"<p>MicroRNAs (miRNAs) are a prominent class of small non-coding RNAs that control gene expression. This comprehensive review explores the intricate roles of miRNAs in metabolism and immunity, as well as the emerging field of immunometabolism. The core of this work delves into the functional and regulatory capabilities of miRNAs, examining their complex influence on glucose and lipid metabolism, as well as their pivotal roles in shaping T-cell development and function. Specifically, this review addresses how miRNAs orchestrate the complex interaction between cellular metabolic processes and immune responses, underscoring the essential nature of these small regulatory molecules in maintaining homeostasis. Finally, we examine the emerging role of Artificial Intelligence (AI) in miRNA research, focusing on how machine learning techniques are revolutionizing the identification and validation of potential miRNA biomarkers. By integrating these diverse aspects, this review underscores the multifaceted roles of miRNAs in biological processes and their significant potential in advancing biomedical research and clinical applications.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":"599 13","pages":"1821-1851"},"PeriodicalIF":3.5,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/1873-3468.70039","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143999019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS LettersPub Date : 2025-04-11DOI: 10.1002/1873-3468.70042
Elina Cernooka, Nikita Zrelovs, Andris Kazaks
{"title":"C-terminal anchor endolysins—proposing a third class of tailed bacteriophage endolysins","authors":"Elina Cernooka, Nikita Zrelovs, Andris Kazaks","doi":"10.1002/1873-3468.70042","DOIUrl":"10.1002/1873-3468.70042","url":null,"abstract":"<p>Endolysins—enzymes produced by tailed bacteriophages to degrade bacterial cell walls—have traditionally been classified as canonical or signal-anchor-release (SAR) endolysins. However, analysis of expanding viral (meta)genomic data has revealed a third class, which we designate as C-terminal anchor (CTA) endolysins. These enzymes feature an N-terminal enzymatic domain, a C-terminal transmembrane domain, and typically lack signal sequences, distinguishing them from SAR endolysins. CTA endolysins span all known enzymatic activities and exhibit diverse architectures, though most have a single transmembrane helix and an N-out, C-in topology, consistent with periplasmic activity. While their functional mechanisms remain to be elucidated, our findings suggest that CTA endolysins are nearly as prevalent as SAR endolysins and represent a distinct, previously unrecognized branch of the endolysin world.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":"599 11","pages":"1499-1508"},"PeriodicalIF":3.5,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143981363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS LettersPub Date : 2025-04-11DOI: 10.1002/1873-3468.70040
Shaima Abdalla, Zary Forghany, Jin Ma, Johan G. Hollander, Ruta Nachane, Karoly Szuhai, Pancras C. W. Hogendoorn, Peter ten Dijke, Dipen Shah, David A. Baker
{"title":"Identification of novel small molecule inhibitors of ETS transcription factors","authors":"Shaima Abdalla, Zary Forghany, Jin Ma, Johan G. Hollander, Ruta Nachane, Karoly Szuhai, Pancras C. W. Hogendoorn, Peter ten Dijke, Dipen Shah, David A. Baker","doi":"10.1002/1873-3468.70040","DOIUrl":"10.1002/1873-3468.70040","url":null,"abstract":"<p>The evolutionarily conserved E-Twenty-Six (ETS) family of transcription factors acts downstream of major signal transduction pathways and plays a pivotal role in tissue development and maintenance. Importantly, their function is frequently corrupted in a substantial proportion of tumour types, and they are also indispensable for angiogenic sprouting, a hallmark of cancer, which is essential for fuelling tumour enlargement and dissemination. Consequently, targeting aberrant ETS activity could potentially represent a precise and effective means by which to block tumour growth. Here, we present proof-of-principle high-throughput screens and an initial characterization of candidate hits, as a methodological and conceptual framework for the identification of novel ETS transcription factor inhibitors, which may ultimately lead to new therapeutic avenues for treating cancer.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":"599 12","pages":"1733-1748"},"PeriodicalIF":3.5,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/1873-3468.70040","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Septin2 regulates ARHGAP25-mediated suppression of lamellipodia formation and cell spreading","authors":"Tomoe Tamura, Emi Umekawa, Mamiko Mori, Mayuko Otsuki, Yoshio Shibagaki, Seisuke Hattori, Takeyuki Sugawara, Koji Saito, Yasutaka Ohta","doi":"10.1002/1873-3468.70041","DOIUrl":"10.1002/1873-3468.70041","url":null,"abstract":"<p>Rho family small GTPases are key regulators of the actin cytoskeletal organization that controls cell morphology, but the regulatory mechanism of Rho small GTPase activity is not fully understood. Here we identified septin2, a component of the septin cytoskeleton, as an interacting protein of ARHGAP25, a GTPase-activating protein for Rho small GTPase Rac, in mammalian cells. ARHGAP25 colocalized with septin2 at lamellipodia, which are actin filament-rich protrusions. Overexpression of ARHGAP25 suppressed Rac-dependent lamellipodia formation and cell spreading, and ARHGAP25-mediated suppression was restored by depletion of septin2. Forced expression of septin2 enhanced ARHGAP25-mediated suppression of cell spreading, and septin2-enhanced suppression was restored by the depletion of ARHGAP25. These results suggest that septin2 controls cell morphology by regulating the function of ARHGAP25.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":"599 11","pages":"1582-1594"},"PeriodicalIF":3.5,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS LettersPub Date : 2025-04-02DOI: 10.1002/1873-3468.70038
Kaiyi Jiang, Jonathan S. Gootenberg, Omar O. Abudayyeh
{"title":"Fanzors, a family of eukaryotic RNA-guided DNA endonucleases","authors":"Kaiyi Jiang, Jonathan S. Gootenberg, Omar O. Abudayyeh","doi":"10.1002/1873-3468.70038","DOIUrl":"10.1002/1873-3468.70038","url":null,"abstract":"<p>Fanzor proteins represent the first confirmed family of RNA-guided DNA endonucleases in eukaryotes. Originally identified in 2013 as TnpB homologs, Fanzors remained functionally uncharacterized until 2023, when three independent research groups demonstrated their activity as programmable nucleases. Comprehensive bioinformatic analysis revealed over 3000 unique Fanzor sequences across diverse eukaryotic phyla and viruses. Fanzors share core mechanisms with their prokaryotic counterparts, utilizing a RuvC domain for DNA cleavage and requiring a Fanzor RNA (ωRNA) for targeting. However, they exhibit distinctive features, including diverse target adjacent motif preferences, extended ωRNA structure, and RuvC domain rearrangements. The eukaryotic origins of Fanzors make them promising tools for mammalian genome editing, with initial studies demonstrating successful editing in human cells without extensive engineering.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":"599 8","pages":"1089-1093"},"PeriodicalIF":3.5,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/1873-3468.70038","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS LettersPub Date : 2025-03-29DOI: 10.1002/1873-3468.70037
Helene Dworak, Tomaz Rozmaric, Johannes Grillari, Mikolaj Ogrodnik
{"title":"Cells of all trades - on the importance of spatial positioning of senescent cells in development, healing and aging.","authors":"Helene Dworak, Tomaz Rozmaric, Johannes Grillari, Mikolaj Ogrodnik","doi":"10.1002/1873-3468.70037","DOIUrl":"10.1002/1873-3468.70037","url":null,"abstract":"<p><p>Biological processes are often spatially regulated, ensuring molecular and cellular events occur in their most strategically advantageous locations. Cellular senescence, marked by cell cycle arrest and hypersecretion, is recognized as an important part of physiological processes like development and healing, but it also contributes to aging and disease. However, the spatial distribution of senescent cells and its physiological and pathological impact remain unclear. Here we compile evidence on senescent cell localization in development, healing, and aging. We emphasize the significance of their spatial patterns and speculate on the effects of disrupted spatial positioning of senescence in relation to pathologies. To summarize the specific spatial functions of senescent cells, we propose to refer to them as 'barrier' and 'conductor' functions. The 'barrier' function of senescent cells, due to their altered morphology and apoptosis resistance, separates tissues and builds a border between two environments. The conductor function, with the secretion of signaling factors, influences the surrounding area and stimulates migration, differentiation, or proliferation, among other processes. Overall, this Review explores the spatial patterning of cellular senescence in biological processes, highlighting its dual roles as 'barrier' and 'conductor' functions, and examines the implications of senescent cell distribution in development, healing, aging, and disease.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7617592/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS LettersPub Date : 2025-03-29DOI: 10.1002/1873-3468.70036
Gagan Sharma, Jennifer R. Deuis, Xinying Jia, Theo Crawford, Sassan Rahnama, Eivind A. B. Undheim, Irina Vetter, Yanni K. -Y. Chin, Mehdi Mobli
{"title":"Refining the NaV1.7 pharmacophore of a class of venom-derived peptide inhibitors via a combination of in silico screening and rational engineering","authors":"Gagan Sharma, Jennifer R. Deuis, Xinying Jia, Theo Crawford, Sassan Rahnama, Eivind A. B. Undheim, Irina Vetter, Yanni K. -Y. Chin, Mehdi Mobli","doi":"10.1002/1873-3468.70036","DOIUrl":"10.1002/1873-3468.70036","url":null,"abstract":"<p>Ion channels are among the main targets of venom peptides. Extensive functional screening has identified a number of these peptides as modulators of the voltage-gated sodium channel subtype Na<sub>V</sub>1.7, a potential target for the treatment of chronic pain. In this study, we used a bioinformatic approach that can automatically identify Na<sub>V</sub>1.7 gating modifier toxins from sequence information alone. The method further enables the incorporation of evolutionarily accessible sequence space in structure–activity relationship studies. The <i>in silico</i> method identified a putative Na<sub>V</sub>1.7 inhibitor, μ-theraphotoxin Cg4a, which we produced recombinantly and confirmed as a Na<sub>V</sub>1.7 inhibitor. Using structural and mutagenesis studies, we propose an improved definition of the pharmacophore of this class of Na<sub>V</sub>1.7 inhibitors, aiding future <i>in silico</i> screening and classification of Na<sub>V</sub>1.7 inhibitors.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":"599 12","pages":"1717-1732"},"PeriodicalIF":3.5,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/1873-3468.70036","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS LettersPub Date : 2025-03-28DOI: 10.1002/1873-3468.70034
Tetsuya Miyamoto, Yurina Iguchi, Ayasa Tada, Mauka Arai, Kumiko Sakai-Kato
{"title":"Characterization and multifunctionality of two amino acid aminotransferases from the hyperthermophile Thermotoga maritima","authors":"Tetsuya Miyamoto, Yurina Iguchi, Ayasa Tada, Mauka Arai, Kumiko Sakai-Kato","doi":"10.1002/1873-3468.70034","DOIUrl":"10.1002/1873-3468.70034","url":null,"abstract":"<p>The hyperthermophile <i>Thermotoga maritima</i> possesses a unique peptidoglycan containing an unusual <span>d</span>-lysine. Previously, we identified enzymes involved in the production of <span>d</span>-lysine and <span>d</span>-glutamate, respectively, but the biosynthetic pathway of <span>d</span>-alanine remains unclear. Herein, we characterized two amino acid aminotransferases, aspartate aminotransferase (TM1255), and alanine aminotransferase (TM1698). TM1255 has specific aminotransferase activities toward <span>l</span>-aspartate and <span>l</span>-glutamate as amino donors, while TM1698 has broad substrate specificity with high activities toward <span>l</span>-alanine and <span>l</span>-aminobutyrate as amino donors. Intriguingly, these two enzymes possess racemase activities toward several amino acids and aspartate 4-decarboxylase activity. The catalytic efficiency of both enzymes was highest for aminotransferase activity, followed by aspartate 4-decarboxylase activity. Therefore, TM1255 and TM1698 are novel multifunctional enzymes that have three different activities.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":"599 8","pages":"1187-1200"},"PeriodicalIF":3.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}