The FEBS journal最新文献

{"title":"Maternal vitamin A deficiency suppresses browning of white adipose tissue in offspring","authors":"Mira Kato-Suzuki,&nbsp;Anju Tsukada,&nbsp;Emi Futagawa,&nbsp;Takito Itoi,&nbsp;Osamu Inanami,&nbsp;Kazuhiro Kimura,&nbsp;Yuko Okamatsu-Ogura","doi":"10.1111/febs.70523","DOIUrl":"10.1111/febs.70523","url":null,"abstract":"<p>Beige adipocytes transiently emerge in white adipose tissue (WAT) during early postnatal development in mice (postnatal browning) independent of sympathetic innervation. However, the underlying mechanism remains unclear. Retinoic acid (RA), an active metabolite of vitamin A, has been reported to promote angiogenesis and browning. In this study, we aimed to elucidate the physiological role of vitamin A in postnatal browning. Maternal vitamin A deficiency, induced by feeding dams a vitamin A-deficient diet during pregnancy and lactation, suppressed browning in the offspring. In contrast, feeding dams a vitamin A-deficient diet only during pregnancy had no effect on the browning of the offspring. Additionally, browning was significantly suppressed by administration of a retinoic acid receptor (RAR) antagonist to pups during either the early (postnatal days 4–12) or late (postnatal days 12–20) lactation period. Maternal vitamin A deficiency and RAR inhibition during early lactation suppressed angiogenesis, which has been suggested to be required for the browning process in adults, whereas RAR inhibition during late lactation did not affect angiogenesis. These findings demonstrate that vitamin A plays a pivotal role in the induction of postnatal browning. Furthermore, we found that vitamin A affects the two-phase process of postnatal browning: promoting angiogenesis and progenitor proliferation in the early lactation period, followed by its action in the late lactation period on the differentiation of beige adipocytes, independently of angiogenesis.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"293 17","pages":"5396-5413"},"PeriodicalIF":4.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147583384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of a cryptic aminoacidic triad involved in the temperature adaptation of GH1 enzymes","authors":"Stefania Digiovanni,&nbsp;Gabriel Oanca,&nbsp;Marco Orlando,&nbsp;Marina Lotti,&nbsp;Johan Åqvist,&nbsp;Marco Mangiagalli","doi":"10.1111/febs.70515","DOIUrl":"10.1111/febs.70515","url":null,"abstract":"<p>Cold-active enzymes exhibit high catalytic activity at low temperatures and an anomalous temperature optimum occurring before the onset of protein unfolding. This study investigates this peculiar property by comparing the functional and structural features of a cold-active glycoside hydrolase family 1 enzyme (M-GH1) with those of its mesophilic counterpart (Pp-GH1). Structural analysis and computational simulations reveal that the thermal profile of M-GH1 is due to a combination of local unfolding and weakened enzyme-substrate interactions. This behavior is attributed to the absence of an amino acid triad comprising M326-W412-F418, which stabilizes the loops surrounding the active site in the mesophilic enzyme. Introducing this triad into M-GH1 through rational mutagenesis yielded a more thermostable variant, whereas reciprocal mutations in Pp-GH1 resulted in a slight decrease of both the optimal temperature of catalysis and thermal stability. Phylogenetic analyses coupled with computational simulations suggest that this flexibility modulation mechanism is not universally conserved across the GH1 family but rather represents a targeted strategy for regulating the dynamics of the catalytic region. Overall, these findings identify a key structural determinant of temperature adaptation within the GH1 family.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"293 17","pages":"5282-5302"},"PeriodicalIF":4.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/febs.70515","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147577424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disruption of iron metabolism resulting from Dmt1/Slc11a2 deficiency compromises Notch protein degradation and transcriptional activation","authors":"Rui Zhang,&nbsp;Somaieh Ahmadian,&nbsp;Jolanda Piepers,&nbsp;Florian Bock,&nbsp;Tom Keulers,&nbsp;Marc A. Vooijs","doi":"10.1111/febs.70522","DOIUrl":"10.1111/febs.70522","url":null,"abstract":"<p>Notch receptor activation requires γ-secretase-mediated release of Notch intracellular domain 1 (NICD1) to regulate gene transcription. Here, we identify the proton-driven solute carrier 11a2 (Slc11a2) or divalent metal transport protein Dmt1 as an inhibitor of Notch signaling via regulating iron homeostasis and lysosomal integrity. Dmt1 loss reduces ferritin levels and increases labile Fe²⁺, causing elevated reactive oxygen species (ROS) and lipid peroxidation. These changes compromise lysosomal function and impair degradation of S3-Val1744 cleaved NICD1, resulting in its accumulation. Dmt1 has isoforms with or without an iron-responsive element (IRE): Re-expressing Dmt1 + IRE robustly increases ferritin heavy-chain (FTH), whereas Dmt1-IRE moderately elevates FTH and ferritin light-chain (FTL), with co-expression further enhancing FTL levels. Restoration of Dmt1 expression rescues ferritin levels, lysosomal activity, and NICD1 degradation while reducing oxidative stress and lipid peroxidation. Notably, Dmt1 deficiency decreases NICD1 binding to RBP-Jκ/CSL and its recruitment to Notch target gene promoters <i>Hes1</i> and <i>Hey1</i>. Collectively, our findings demonstrate that Dmt1 regulates lysosomal function through iron homeostasis and that lysosomal dysfunction from Dmt1 loss impairs NICD1 degradation and disrupts Notch signaling, linking cellular iron metabolism and Notch pathway activity.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"293 17","pages":"5383-5395"},"PeriodicalIF":4.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/febs.70522","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147577419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cryo-EM structures of multiple-peptide resistance factor (MprF) from Pseudomonas aeruginosa","authors":"Shaileshanand Jha,&nbsp;Kutti R. Vinothkumar","doi":"10.1111/febs.70519","DOIUrl":"10.1111/febs.70519","url":null,"abstract":"<p>Aminoacylation of the lipid head group in many bacteria is carried out by bi-functional enzymes called MprF, which encode a soluble synthase domain that typically transfers lysine or alanine from a tRNA to lipid head groups. The modified lipid is subsequently translocated across the leaflets by a transmembrane domain. This modification of lipids probably evolved to adapt to the environment where the microbes reside. Here, we describe the cryo-EM structures of MprF enzyme from <i>Pseudomonas aeruginosa</i>, revealing a dimeric enzyme with a distinct architecture when compared with the homologous <i>Rhizobium</i> enzymes, and validate this arrangement with biochemical analyses. The cryo-EM maps and the models in detergent micelle and nanodisc reveal a conformational change of the terminal helix of the synthase domain, highlighting the dynamic elements in the enzyme that might facilitate catalysis. Several lipid-like densities are observed in the cryo-EM maps, which might indicate the path taken by the lipids, coupling the function of the two domains. The structures allow postulation of the binding modes of tRNA and lipid transport, and suggest that the mobile secondary structural elements in the synthase domain might play a mechanistic role in these functions.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"293 17","pages":"5318-5339"},"PeriodicalIF":4.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/febs.70519","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148007705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pml loss worsens NEK1-linked ALS and Pml induction drives NEK1 degradation, precluding disease onset","authors":"Panagiota Georgiadou,&nbsp;Bahriye Erkaya,&nbsp;Michiko Niwa-Kawakita,&nbsp;Merve Oltan,&nbsp;Yigit Kemal Keskin,&nbsp;Egemen Sahin,&nbsp;Harun Öztürk,&nbsp;Fatmanur Tiryaki,&nbsp;Kutay Yildiz,&nbsp;Idil Özgenç,&nbsp;Ezgi Odabasi,&nbsp;Emre Pekbilir,&nbsp;Sukru Anil Dogan,&nbsp;Valérie Lallemand-Breitenbach,&nbsp;Stephanie Vargas,&nbsp;Alain Prochiantz,&nbsp;Elif Nur Firat-Karalar,&nbsp;Hugues de Thé,&nbsp;Umut Sahin","doi":"10.1111/febs.70487","DOIUrl":"10.1111/febs.70487","url":null,"abstract":"<p>Germinal mono-allelic loss-of-function mutations of <i>NEK1</i> drive amyotrophic lateral sclerosis (ALS) at variable penetrance, presumably through haploinsufficiency. Modeling the ALS-associated Arg812Ter mutation in mice revealed that the resulting truncated Nek1 (Nek1^t) is aggregation-prone, particularly in alpha-motoneurons (αMNs), and drives canonical ALS symptoms when bi-allelically expressed (<i>Nek1</i>^<i>t/t</i><i>)</i>. Promyelocytic leukemia (<i>Pml</i>) ablation allows for ALS symptoms to occur even in heterozygote <i>Nek1</i>^<i>wt/t</i> animals, mimicking the human situation. <i>Pml</i> precludes disease occurrence by promoting SUMO-facilitated degradation of Nek1^t proteins through PML nuclear bodies (NBs). Conversely, <i>Pml</i> induction, achieved by activating the interferon pathway via poly(I:C) treatment, clears Nek1^t puncta in αMNs, dramatically reducing ALS-associated symptoms and extending survival by 5 months. Our studies highlight the role of mutant NEK1 expression in ALS pathogenesis and identifies activation of interferon pathways as a candidate therapeutic strategy that promotes <i>Pml-</i>triggered SUMOylation/degradation of toxic misfolded proteins <i>in vivo</i>, yielding dramatic clinical improvement. These observations provide strong proof-of-concept support to validate PML as a relevant therapeutic target in neurodegenerative conditions associated with protein misfolding and putative aggregation.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"293 17","pages":"5170-5185"},"PeriodicalIF":4.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147392132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extended motif recognition tunes WW domain affinity in MAGI–IQSEC complexes","authors":"Jinchao Wang,&nbsp;Yuting Li,&nbsp;Yanze Wu,&nbsp;Lin Lin,&nbsp;Jinwei Zhu","doi":"10.1111/febs.70509","DOIUrl":"10.1111/febs.70509","url":null,"abstract":"<p>Many proteins containing WW domains interact with proline-rich PPxY motifs, raising questions regarding how they achieve specificity in cellular contexts. Here, we characterize the WW domain-mediated interactions between the MAGI and IQSEC protein families, which play critical roles in neurodevelopment and synaptic signaling. The high-resolution crystal structure of the MAGI3–IQSEC3 complex reveals that an extended sequence C terminus to the canonical PPxY motif in IQSEC3 engages a previously uncharacterized binding site on the WW1 domain of MAGI3. This extension interface enhances binding affinity by dozens-fold, and mutagenesis of key residues within this site abrogates complex formation, demonstrating its functional necessity. This bipartite recognition mode is evolutionarily conserved across MAGI and IQSEC family members. Our work elucidates the structural basis governing MAGI–IQSEC assembly and establishes a generalizable model whereby motif extensions enable high-affinity, specific target selection by WW domains, with broad implications for modular domain-mediated signaling networks.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"293 17","pages":"5241-5254"},"PeriodicalIF":4.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147501215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial transfer in acute myeloid leukaemia and multiple myeloma: Mechanisms, consequences and potential therapeutic opportunities","authors":"Ebubechukwu Nwarunma,&nbsp;Mark T. S. Williams","doi":"10.1111/febs.70544","DOIUrl":"10.1111/febs.70544","url":null,"abstract":"<p>Haematological malignancies, such as acute myeloid leukaemia (AML) and multiple myeloma (MM), which develop from malignant transformations within the bone marrow, represent the most critical unmet needs in the haemato-oncology field. Sub-optimal clinical outcomes in patients with AML and MM are often driven by resistance to chemotherapy. It is well established that cells within the bone marrow microenvironment (BMME) support the proliferation and survival of these blood cancer cells. One of the mechanisms by which these BMME-resident cells support the malignant cells is through horizontal mitochondrial transfer (HMT), a mechanism well documented as occurring under steady-state conditions as well as in many cancers. Recent research implicates mitochondrial transfer in BMME-driven chemoresistance in AML and MM. In this review, we critically analyse current understanding of the role of HMT in supporting the survival and proliferation of AML and MM cells, as well as driving resistance to cytotoxic effects of chemotherapy. We further elucidate various mechanisms, molecular triggers, functional consequences, and therapeutic implications for HMT in AML and MM. Our review also highlights unanswered questions within the HMT field and provides a theoretical basis for further study, giving direction on what is important in translating this knowledge into effective future therapeutic strategies.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"293 17","pages":"5107-5120"},"PeriodicalIF":4.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/febs.70544","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147647985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A quantitative dissection of the DNA-binding properties of pathogenic GATA1 mutants","authors":"Kaoru Takasaki","doi":"10.1111/febs.70614","DOIUrl":"10.1111/febs.70614","url":null,"abstract":"<p>Transcription factors are modulated by a precisely coordinated set of conditions, including cell context, target sequences and their accessibility, and co-factor recruitment. Disruption to any of these conditions can dramatically affect transcription factor activity, but quantitatively characterizing the consequences of individual mutations—either in the transcription factors themselves or in their target sequences—has remained a technical challenge. Zambo <i>et al.</i> present an innovation on their native holdup assay that measures DNA–protein binding activity under physiologic or near-physiologic conditions and use mutant GATA1-<i>ATP2B4</i> binding as an illustrative example. This technique holds promise for uncovering the molecular mechanisms underlying genetically-driven diseases.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"293 17","pages":"5140-5144"},"PeriodicalIF":4.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/febs.70614","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148145489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tyrosine residues at the substrate binding site in human NQO1 homodimer: Protein conformational dynamics and optimization of substrate binding geometry","authors":"Maribel Rivero,&nbsp;Juan Luis Pacheco-Garcia,&nbsp;Pavla Vankova,&nbsp;Dmitry Loginov,&nbsp;Isabel Quereda-Moraleda,&nbsp;Jose Manuel Martin-Garcia,&nbsp;Petr Man,&nbsp;Angel Luis Pey,&nbsp;Milagros Medina","doi":"10.1111/febs.70511","DOIUrl":"10.1111/febs.70511","url":null,"abstract":"<p>Human NQO1 is a homodimeric flavoenzyme essential for the redox metabolism of many substances and implicated in major global health challenges such as cancer and Alzheimer's disease. X-ray crystallographic studies have identified several residues within its substrate binding site (including Tyr126 and Tyr128) that may regulate catalytic competent binding of substrates, cofactor redox properties, half-site reactivity, and/or functional inter-active site negative cooperativity. To elucidate the functional role of Tyr126 and Tyr128, we generated point mutants at these positions and assessed their dynamics and kinetic properties. Hydrogen-deuterium exchange coupled to mass spectrometry revealed that non-conservative mutations, particularly at Tyr126, notably disrupted dynamics not only within the substrate binding site but also in structural elements connecting the two active sites of the NQO1 homodimer. Rapid-mixing pre-steady-state kinetics experiments of the reduction of NQO1 by NAD(P)H showed that mutations to Phe caused a mild decrease in hydride transfer (HT) efficiency from the coenzyme to the FAD cofactor. In contrast, mutations to Ala resulted in a significantly greater impact and mutations to Glu nearly abolished HT. Despite these effects, some mutations moderately affected the non-synchronous catalysis between the two alternating active sites, but hardly produced an impact on the selectivity for NADPH <i>versus</i> NADH as hydride donor coenzymes. However, all variants exhibited markedly impaired enzyme turnover, highlighting alterations in the enzyme's substrate specificity toward quinones. The data presented here demonstrate that Tyr126 and Tyr128 optimize both substrate binding geometry as well as overall enzyme conformational dynamics during the asymmetric catalytic cycle of the NQO1 homodimer.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"293 17","pages":"5255-5281"},"PeriodicalIF":4.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/febs.70511","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147517859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The interaction between NPMc+ and Orai1 induces abnormal calcium influx to facilitate leukemogenesis","authors":"Wenhao Zhang,&nbsp;Chuangxuan Liang,&nbsp;Lulu Zhang,&nbsp;Xinglin Liu,&nbsp;Zhenyu Zhang,&nbsp;Huarong Guo,&nbsp;Jie Jia,&nbsp;Xin Chen,&nbsp;Hongxin Shang,&nbsp;Xuena Zheng,&nbsp;Jun Qin,&nbsp;Shan Li,&nbsp;Danwen Liu,&nbsp;Fuyun Wu","doi":"10.1111/febs.70508","DOIUrl":"10.1111/febs.70508","url":null,"abstract":"<p>Nucleophosmin 1 (NPM1) is a ubiquitously expressed phosphoprotein, mainly located in the nucleolus. It is overexpressed in solid tumors and considered a key target in cancer therapy. NPM1 mutations are the most common genetic abnormalities in acute myeloid leukemia (AML), where they are found in about 30% of patients. In AML, NPM1 mutations result in the cytoplasmic localization of the mutant protein NPMc+. Although NPM1 mutations are known to drive AML, the underlying mechanisms are not fully understood. In this study, we found that primary leukemia cells from NPM1-mutated AML patients exhibited elevated intracellular calcium levels compared with cells from NPM1 wild-type AML patients. Our investigation revealed that NPMc+ interacts with the calcium channel Orai1, disrupting calcium homeostasis in AML cells. Notably, we identified that the N-terminal region of NPM1 contains a calcium-binding domain that directly interacts with Orai1, facilitating calcium influx. Targeting NPMc+, Orai1, or the NPMc+/Orai1 complex using small-molecule inhibitors significantly reduced calcium influx, inhibited calcium-related signaling pathways, and suppressed the proliferation of NPM1-mutated AML cells. These findings uncover a novel mechanism in which NPMc+ interacts with Orai1, disrupting calcium homeostasis and promoting AML progression. This presents a promising therapeutic strategy targeting the NPMc+/Orai1-mediated calcium imbalance in NPM1-mutated AML.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"293 17","pages":"5221-5240"},"PeriodicalIF":4.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147505956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}