FEBS Letters最新文献

{"title":"Leucine-rich glioma inactivated 1 (LGI1) is a ganglioside-binding protein.","authors":"Kévin Debreux, Christian Lévêque, Fodil Azzaz, Marion Sangiardi, Sarosh R Irani, Michael Seagar, Jacques Fantini, Oussama El Far","doi":"10.1002/1873-3468.70465","DOIUrl":"https://doi.org/10.1002/1873-3468.70465","url":null,"abstract":"<p><p>In Lgi1^-/- mice, increased neuronal excitability is accompanied by a marked decrease in Kv1 channels, but the mechanism linking LGI1 loss to reduced ion channel expression remains unknown. We show that LGI1 contains multiple conserved canonical ganglioside-binding domains (GBDs) and that GT1b copurifies with LGI1 antibodies from native rat brain extracts. Recombinant LGI1 bound ganglioside-containing liposomes, and the ganglioside-binding capacity of surface-exposed GBD peptide sequences was confirmed experimentally. These findings suggest LGI1 interacts with gangliosides and may help organize lipid membrane platforms that accommodate functional protein complexes. We hypothesize that loss of LGI1 destabilizes these platforms, contributing to the reduced ion channel expression observed in Lgi1^-/- mice.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148967242","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}

{"title":"L-aspartate oxidase provides new insights into fumarate reduction in anaerobic darkness in Synechocystis sp. PCC6803.","authors":"Kateryna Kukil, Jeffrey A Hawkes, Cecilia Blikstad, Pia Lindberg","doi":"10.1002/1873-3468.70460","DOIUrl":"10.1002/1873-3468.70460","url":null,"abstract":"<p><p>Cyanobacteria are promising microbial hosts for production of succinate, a central metabolite of the tricarboxylic acid (TCA) cycle, which cyanobacteria can secrete during anoxic fermentation. To investigate the route for succinate formation, we generated strains of Synechocystis PCC6803 lacking subunits of the succinate dehydrogenase complex (SDH). During dark anaerobic fermentation, the deletion strains show higher succinate accumulation than the wild type, indicating succinate dehydrogenase activity of SDH rather than fumarate reduction. Another potential route for succinate formation from fumarate is as a byproduct of the L-aspartate oxidase (Laspo) reaction. Using purified SynLaspo, we show that in addition to L-aspartate oxidation, the enzyme exhibits L-aspartate-fumarate oxidoreductase activity, generating succinate. This work contributes to the understanding of the cyanobacterial TCA cycle.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148967262","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}

{"title":"Structural insights into the development of inhibitors for inositol phosphate kinases","authors":"Huanchen Wang","doi":"10.1002/1873-3468.70280","DOIUrl":"10.1002/1873-3468.70280","url":null,"abstract":"<p>The inositol phosphate signaling pathway has emerged as a compelling therapeutic target in a broad range of diseases, including osteoporosis, viral infections, metabolic disorders, and cancer metastasis. Inositol phosphates regulate essential cellular processes such as insulin signaling, nucleotide synthesis, DNA damage response, and phosphate homeostasis. Given this wide spectrum of physiological roles, the kinases responsible for inositol phosphate biosynthesis—namely IP3Ks, IPMK, ITPK1, IP5-2 K, IP6Ks, and PPIP5Ks—have attracted increased interest over the past decade. Accumulating evidence supports their potential as drug targets in the treatment of obesity, cancer, and aging-related conditions. In this review, structure-guided strategies, particularly those informed by high-resolution crystal structures, are examined for their role in accelerating the discovery and development of small-molecule inhibitors targeting inositol phosphate kinases. Structural insights, advances in therapeutic development, and future directions for improving inhibitor specificity and efficacy are discussed.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":"600 17","pages":"2344-2360"},"PeriodicalIF":3.0,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12823050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146009414","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":"Protein pyrophosphorylation by inositol pyrophosphates — detection, function, and regulation","authors":"Sarah Lampe,&nbsp;Tanmay Kumar Mohanty,&nbsp;Rashna Bhandari,&nbsp;Dorothea Fiedler","doi":"10.1002/1873-3468.70240","DOIUrl":"10.1002/1873-3468.70240","url":null,"abstract":"<p>Protein pyrophosphorylation is an emerging, unusual posttranslational modification. This signaling mechanism can be driven by inositol pyrophosphate messengers, which can convert a prephosphorylated protein to the corresponding pyrophosphoprotein. Endogenous protein pyrophosphorylation influences various cellular processes and signaling pathways, including the regulation of rRNA synthesis and the modulation of vesicular trafficking. Herein, we will summarize the current detection and analysis methods that have established the occurrence of pyrophosphorylation. These methods have also been used to explore the effects of pyrophosphorylation on protein structure and function. Putative mechanisms for the regulation of this intriguing, understudied modification will be discussed. Finally, the future needs for this developing area of signal transduction research are highlighted.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":"600 17","pages":"2420-2436"},"PeriodicalIF":3.0,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/1873-3468.70240","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145660794","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":"IPMK at the crossroads of cellular signaling in health and disease","authors":"Sera Kim,&nbsp;Jaeseung Ryu,&nbsp;Jae Yeong Park,&nbsp;Ji Kwang Kim,&nbsp;Lauren S. Whang,&nbsp;Seyun Kim","doi":"10.1002/1873-3468.70256","DOIUrl":"10.1002/1873-3468.70256","url":null,"abstract":"<p>Inositol phosphates (InsPs) represent a conserved class of water-soluble signaling molecules found in all eukaryotes. Their biosynthesis involves a tightly regulated enzymatic network, with inositol polyphosphate multikinase (IPMK) functioning as a pivotal catalytic hub. IPMK exhibits broad substrate specificity, phosphorylating various InsPs and phosphatidylinositol 4,5-bisphosphate. Beyond its enzymatic activity, IPMK also modulates key signaling pathways through noncatalytic mechanisms, including direct interactions with protein partners. This review highlights the functional attributes of IPMK, its diverse roles in cellular physiology and disease, and outlines current challenges and future directions in IPMK research.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":"600 17","pages":"2361-2378"},"PeriodicalIF":3.0,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/1873-3468.70256","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145911213","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":"Three phosphatase families form a community: The phosphohydrolases that act upon inositol pyrophosphates","authors":"Ronda J. Rolfes","doi":"10.1002/1873-3468.70394","DOIUrl":"10.1002/1873-3468.70394","url":null,"abstract":"<p>Inositol pyrophosphates (PP-InsP) are high energy signaling molecules that play important roles in eukaryotes. They are synthesized from inositol polyphosphates by kinases that add a diphosphate (β phosphate) at one or more positions on the <i>myo-</i>inositol ring. The focus of this review is on the phosphatases specific for the β phosphate. These enzymes are members of three different families of phosphohydrolases: the histidine acid phosphatase family that is specific for β phosphate on 1C, the cysteine phosphatase family that is specific for the diphosphate on 5C, and the Nudix family that is promiscuous both in terms of the position of the diphosphate on PP-InsPs and recognition of a range of molecules with phosphoanhydride linkages. These three families of phosphatases share overlapping PP-InsP substrates, and as a community of enzymes they have a combined influence on PP-InsP pools, impacting cellular processes and phenotypes. Each phosphatase family is discussed from biochemical perspectives (enzyme structure, substrate preferences, kinetic properties), distribution across eukaryotes (evolutionary, phylogenetic), and the similarities and differences in the affected cellular processes across fungi, animals, and plants.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":"600 17","pages":"2579-2614"},"PeriodicalIF":3.0,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/1873-3468.70394","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148316616","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":"Phosphoinositides and inositol phosphates—functions and cellular dynamics","authors":"Feng Rao,&nbsp;Volker Haucke","doi":"10.1002/1873-3468.70419","DOIUrl":"https://doi.org/10.1002/1873-3468.70419","url":null,"abstract":"&lt;p&gt;Inositol phosphates (IPs) and phosphoinositides (PIPs) are evolutionarily ancient eukaryotic signaling molecules derived from the six-carbon cyclic polyalcohol myo-inositol. Whereas phosphoinositides are membrane-anchored lipids that regulate compartmental signaling and membrane trafficking [&lt;span&gt;[1, 2]&lt;/span&gt;], soluble inositol phosphates, including highly phosphorylated inositol pyrophosphates, act as versatile metabolic messengers in the nucleus and cytosol [&lt;span&gt;[3, 4]&lt;/span&gt;]. This Special Issue of &lt;i&gt;FEBS Letters&lt;/i&gt;, ‘Inositol phosphates and phosphoinositides—functions and cellular dynamics’, brings together complementary review articles that highlight how soluble inositol phosphates (IPs, also abbreviated as InsPs), inositol pyrophosphates (PP-IPs or PP-InsPs), and phosphoinositides (PIPs) form an interconnected signaling network with fundamental and translational relevance. The contributions span structural enzymology, analytical methodology, chemical biology, molecular mechanisms of IP/PIP-dependent protein complexes, and their roles in stress responses, development, immunity, and disease, in organisms ranging from plants to mammals.&lt;/p&gt;&lt;p&gt;A unifying theme emerging from the Special Issue is that cellular inositol signaling cannot be understood in terms of isolated pathways. Wang's [&lt;span&gt;[5]&lt;/span&gt;] review on inositol phosphate kinases emphasizes that IPs are generated via at least two interconnected routes in mammalian cells: a canonical lipid pathway initiated by receptor-stimulated phospholipase C (PLC) hydrolysis of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P&lt;sub&gt;2&lt;/sub&gt;) and a &lt;i&gt;de novo&lt;/i&gt; cytosolic route from glucose, with extensive reversibility and compensation among kinase and phosphatase steps. IP&lt;sub&gt;3&lt;/sub&gt; generated from PI(4,5)P&lt;sub&gt;2&lt;/sub&gt; serves not only as a second messenger for Ca&lt;sup&gt;2+&lt;/sup&gt; release but also as the entry point into a cascade of higher phosphorylated IPs, culminating in IP&lt;sub&gt;6&lt;/sub&gt; and PP-IPs, such as 5-IP&lt;sub&gt;7&lt;/sub&gt; and 1,5-IP&lt;sub&gt;8&lt;/sub&gt;. As reviewed in detail by the Kim and Fu laboratories, the physiological functions and disease relevance of inositol polyphosphate multikinase (IPMK) and IP6Ks are pleiotropic and versatile, specifically during adaptive responses throughout various tissues/organs [&lt;span&gt;[6, 7]&lt;/span&gt;], opening promising therapeutic avenues in fighting major diseases like cancer, diabetes, and neurodegeneration.&lt;/p&gt;&lt;p&gt;Another emerging theme is the metabolic crosstalk between inositol phosphates and phosphoinositide lipids: IPMK, for example, phosphorylates both soluble IPs and PI(4,5)P&lt;sub&gt;2&lt;/sub&gt;, with the later contributing to PI(3,4,5)P&lt;sub&gt;3&lt;/sub&gt; production and thus linking nuclear and cytosolic IP pools to lipid signaling at membranes [&lt;span&gt;[6]&lt;/span&gt;]. Reviews in this issue further illustrate that changes in the level of one metabolite (e.g., IP&lt;sub&gt;7&lt;/sub&gt;) often propagate through the network to affect others (e.g., IP&lt;sub&gt;8&lt;/sub&gt;, PI(3,4,5)P&lt;sub&gt;3&lt;/sub&gt;), so ","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":"600 17","pages":"2339-2343"},"PeriodicalIF":3.0,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/1873-3468.70419","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148962497","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":"Phosphoinositides in membrane remodeling during infections and cellular stresses","authors":"Carla Alemany,&nbsp;Etienne Morel","doi":"10.1002/1873-3468.70213","DOIUrl":"10.1002/1873-3468.70213","url":null,"abstract":"<p>Phosphoinositides, a versatile class of phosphorylated phosphatidylinositols, are emerging as central orchestrators of cellular stress responses. Beyond defining the organization and identity of endomembranes, these dynamic lipids act as highly adaptable signaling hubs that integrate diverse stress cues, from nutrient deprivation and mechanical strain to osmotic imbalance and DNA damage. Across evolution—from unicellular organisms to mammals—they drive conserved adaptation programs, including vacuolar remodeling, endosomal trafficking, and autophagosome biogenesis, through a finely tuned metabolism governed by an intricate network of kinases, phosphatases, and regulatory partners. Recent advances uncover how compartment-specific regulation, enzymatic diversity, and organelle crosstalk converge on phosphoinositide signaling, revealing these lipids as not only molecular adaptors but also promising therapeutic entry points in diseases marked by defective stress resolution. This review synthesizes emerging insights into the multifaceted roles of phosphoinositides in mobilizing membranes under stress, with a focus on mechanistic principles and recent research.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":"600 17","pages":"2470-2489"},"PeriodicalIF":3.0,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/1873-3468.70213","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145408588","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":"Phosphatidylinositol 4-kinase as a target of pathogens—friend or foe?","authors":"Ana C. Mendes,&nbsp;Guilherme M. Azevedo,&nbsp;Amanda P. Barcellos,&nbsp;Diana Bahia","doi":"10.1002/1873-3468.70216","DOIUrl":"10.1002/1873-3468.70216","url":null,"abstract":"<p>Phosphatidylinositol 4-kinases (PI4Ks) are pivotal enzymes responsible for the generation of phosphatidylinositol 4-phosphate (PI4P), a key precursor involved in various cellular signalling pathways that regulate vesicular trafficking, Golgi maintenance and intracellular communication. Conserved across eukaryotic species, PI4Ks exist in distinct isoforms with specific localisations and functions, ranging from plasma membrane dynamics to endosomal trafficking and autophagy regulation. Notably, numerous pathogens, including viruses, bacteria and parasites, have evolved mechanisms to hijack host PI4Ks, thereby facilitating intracellular replication and survival. For example, RNA viruses within the <i>Flaviviridae</i> and <i>Coronaviridae</i> families recruit PI4Ks to remodel host membranes for the assembly of replication complexes. Similarly, intracellular bacteria such as <i>Salmonella</i> and <i>Legionella</i> manipulate PI4P-enriched compartments to evade host defences and promote replication. Due to their central roles in both normal cellular physiology and infection, PI4Ks have emerged as promising therapeutic targets. A variety of inhibitors, including ATP-competitive compounds, have been developed and evaluated for their antiviral, antibacterial and antiparasitic potential. Nevertheless, challenges related to selectivity and toxicity remain. Recent advances include the identification of inhibitors effective against <i>Plasmodium</i> species and the development of compounds targeting PI4KIIIβ in infections with viruses such as hepatitis C and coronaviruses. This review highlights the dual role of PI4Ks as essential cellular regulators and exploitable pathogen cofactors, underscoring their potential as drug targets. Continued investigation into the structure, function and inhibition of PI4Ks may enable the development of selective therapeutic strategies for infectious diseases while minimising off-target effects on host cells.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":"600 17","pages":"2547-2563"},"PeriodicalIF":3.0,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/1873-3468.70216","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145494831","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":"The power of five – inositol polyphosphate 5-phosphatase gene mutations at the intersection of development and disease","authors":"Meagan J. McGrath,&nbsp;Elizabeth M. Davies,&nbsp;Lisa M. Ooms,&nbsp;Randini Nanayakkara,&nbsp;Rajendra Gurung,&nbsp;Emily I. Jones,&nbsp;Christina A. Mitchell","doi":"10.1002/1873-3468.70247","DOIUrl":"10.1002/1873-3468.70247","url":null,"abstract":"<p>Phosphoinositides are transient signaling lipids, derived from the reversible phosphorylation of phosphatidylinositol on intracellular membranes, which serve as master regulators of many essential cellular functions. Seven distinct phosphoinositide species require precise spatiotemporal control, which is regulated by specific phosphatidylinositol kinases and phosphatases. Here, we review one such family, the inositol polyphosphate 5-phosphatases, which comprise 10 mammalian enzymes that dephosphorylate the 5-position phosphate group from the inositol head group of PtdIns(4,5)<i>P</i>₂, PtdIns(3,5)<i>P</i>₂, and/or PtdIns(3,4,5)<i>P</i>₃. Despite overlapping substrate specificities, the 5-phosphatases play nonredundant roles, including in development, as demonstrated by murine and zebrafish knockout studies. Mutations in several 5-phosphatase family members are associated with multisystem developmental and congenital syndromes. Associations between 5-phosphatase gene variants and diabetes and metabolic syndrome, neurodegenerative disease, and in rare cases cancer, are also emerging. Here, we provide a comprehensive discussion of the latest advances in this field, including updates on disease modeling and mechanisms.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":"600 17","pages":"2615-2660"},"PeriodicalIF":3.0,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/1873-3468.70247","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145774157","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}