The FEBS journal最新文献

{"title":"Exploring the role of AMPA receptor auxiliary proteins in synaptic functions and diseases.","authors":"Mohammad Qneibi, Sosana Bdir, Mohammad Bdair, Samia Ammar Aldwaik, Maram Heeh, Dana Sandouka, Tala Idais","doi":"10.1111/febs.17287","DOIUrl":"https://doi.org/10.1111/febs.17287","url":null,"abstract":"<p><p>α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) ionotropic glutamate receptors (AMPARs) mediate rapid excitatory synaptic transmission in the mammalian brain, primarily driven by the neurotransmitter glutamate. The modulation of AMPAR activity, particularly calcium-permeable AMPARs (CP-AMPARs), is crucially influenced by various auxiliary subunits. These subunits are integral membrane proteins that bind to the receptor's core and modify its functional properties, including ion channel kinetics and receptor trafficking. This review comprehensively catalogs all known AMPAR auxiliary proteins, providing vital insights into the biochemical mechanisms governing synaptic modulation and the specific impact of CP-AMPARs compared to their calcium-impermeable AMPA receptor (CI-AMPARs). Understanding the complex interplay between AMPARs and their auxiliary subunits in different brain regions is essential for elucidating their roles in cognitive functions such as learning and memory. Importantly, alterations in these auxiliary proteins' expression, function or interactions have been implicated in various neurological disorders. Aberrant signaling through CP-AMPARs, in particular, is associated with severe synaptic dysfunctions across neurodevelopmental, neurodegenerative and psychiatric conditions. Targeting the distinct properties of AMPAR-auxiliary subunit complexes, especially those involving CP-AMPARs, could disclose new therapeutic strategies, potentially allowing for more precise interventions in treating complex neuronal disorders.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142407353","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":"Hemin-induced platelet activation is regulated by the ACKR3 chemokine surface receptor and has implications for passivation of vulnerable atherosclerotic plaques.","authors":"Zoi Laspa, Valerie Dicenta-Baunach, David Schaale, Manuel Sigle, Ravi Hochuli, Tatsiana Castor, Alp Bayrak, Tobias Harm, Karin Anne Lydia Müller, Thanigaimalai Pillaiyar, Stefan Laufer, Anne-Katrin Rohlfing, Meinrad Paul Gawaz","doi":"10.1111/febs.17294","DOIUrl":"https://doi.org/10.1111/febs.17294","url":null,"abstract":"<p><p>In vulnerable atherosclerotic plaques, intraplaque hemorrhages (IPH) result in hemolysis of red blood cells and release of hemoglobin and free hemin. Hemin activates platelets and leads to thrombosis. Agonism of the inhibitory platelet receptor ACKR3 inhibits hemin-dependent platelet activation and thrombus formation. To characterize the effect of hemin and ACKR3 agonism on isolated human platelets, multi-color flow cytometry and classical experimental setup such as light transmission aggregometry and a flow chamber assay were used. Hemin induces platelet aggregation and ex vivo platelet-dependent thrombus formation on immobilized collagen under a low shear rate of 500 s^-1, indicating that free hemin is a strong activator of platelet-dependent thrombosis. Recently, we described that ACKR3 is a prominent inhibitory receptor of platelet activation. Specific ACKR3 agonists but not conventional antiplatelet compounds such as COX-1 inhibitor (indometacin), ADP-receptor blocker (cangrelor), or PAR1 inhibitor (ML161) inhibit both hemin-dependent aggregation and thrombus formation. To further characterize the effect of hemin on platelet subpopulations, we established a multi-color flow cytometry assay. We found that hemin induces procoagulant (CD42b^pos/PAC-1^neg/AnnexinV^pos), aggregatory (CD42b^pos/PAC-1^pos/AnnexinV^neg), and inflammatory (CD42b^pos/CXCR4^pos/ACKR3^pos/AnnexinV^pos) platelet subpopulations. Treatment with ACKR3 agonists significantly decreased the formation of procoagulant and ACKR3^pos platelets in response to hemin. We conclude that hemin is a strong activator for the formation of procoagulant platelets and thrombus formation which is dependent on the function of ACKR3. Activation of ACKR3 using specific agonists may offer a therapeutic strategy to regulate the vulnerability of atherosclerotic plaques in areas of IPH.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142484732","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":"Biochemical plasticity of the Escherichia coli CRISPR Cascade revealed by in vitro reconstitution of Cascade activities from purified Cas proteins.","authors":"Sofia Lemak, Greg Brown, Kira S Makarova, Eugene V Koonin, Alexander F Yakunin","doi":"10.1111/febs.17295","DOIUrl":"https://doi.org/10.1111/febs.17295","url":null,"abstract":"<p><p>The most abundant clustered regularly interspaced short palindromic repeats (CRISPR) type I systems employ a multisubunit RNA-protein effector complex (Cascade), with varying protein composition and activity. The Escherichia coli Cascade complex consists of 11 protein subunits and functions as an effector through CRISPR RNA (crRNA) binding, protospacer adjacent motif (PAM)-specific double-stranded DNA targeting, R-loop formation, and Cas3 helicase-nuclease recruitment for target DNA cleavage. Here, we present a biochemical reconstruction of the E. coli Cascade from purified Cas proteins and analyze its activities including crRNA binding, dsDNA targeting, R-loop formation, and Cas3 recruitment. Affinity purification of 6His-tagged Cas7 coexpressed with untagged Cas5 revealed the physical association of these proteins, thus producing the Cas5-Cas7 subcomplex that was able to bind specifically to type I-E crRNA with an efficiency comparable to that of the complete Cascade. The crRNA-loaded Cas5-7 was found to bind specifically to the target dsDNA in a PAM-independent manner, albeit with a lower affinity than the complete Cascade, with both spacer sequence complementarity and repeat handles contributing to the DNA targeting specificity. The crRNA-loaded Cas5-7 targeted the complementary dsDNA with detectable formation of R-loops, which was stimulated by the addition of Cas8 and/or Cas11 acting synergistically. Cascade activity reconstitution using purified Cas5-7 and other Cas proteins showed that Cas8 was essential for specific PAM recognition, whereas the addition of Cas11 was required for Cas3 recruitment and target DNA nicking. Thus, although the core Cas5-7 subcomplex is sufficient for specific crRNA binding and basal DNA targeting, both Cas8 and Cas11 make unique contributions to efficient target recognition and cleavage.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142396479","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":"USP15 inhibits hypoxia-induced IL-6 signaling by deubiquitinating and stabilizing MeCP2.","authors":"Zi-Tong Zhang, Shu-Xuan Niu, Chen-Hao Yu, Shi-Yuan Wan, Jiao Wang, Cheng-Yu Liu, Ling Zheng, Kun Huang, Yu Zhang","doi":"10.1111/febs.17282","DOIUrl":"https://doi.org/10.1111/febs.17282","url":null,"abstract":"<p><p>Methyl-CpG binding protein 2 (MeCP2) is an important X-linked DNA methylation reader and a key heterochromatin organizer. The expression level of MeCP2 is crucial, as indicated by the observation that loss-of-function mutations of MECP2 cause Rett syndrome, whereas an extra copy spanning the MECP2 locus results in MECP2 duplication syndrome, both being progressive neurodevelopmental disorders. Our previous study demonstrated that MeCP2 protein expression is rapidly induced by renal ischemia-reperfusion injury (IRI) and protects the kidney from IRI through transcriptionally repressing the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 signaling pathway. However, the mechanisms underlying the upregulation of MeCP2 have remained elusive. Here, by using two hypoxia cell models, hypoxia and reoxygenation and cobalt chloride stimulation, we confirmed that the removal of lysine 48-linked ubiquitination from MeCP2 prevented its proteasome-dependent degradation under hypoxic conditions. Through unbiased screening based on a deubiquitinating enzymes library, we identified ubiquitin-specific protease 15 (USP15) as a stabilizer of MeCP2. Further studies revealed that USP15 could attenuate hypoxia-induced MeCP2 degradation by cleaving lysine 48-linked ubiquitin chains from MeCP2, primarily targeting its C-terminal domain. Consistently, USP15 inhibited hypoxia-induced signal transducer and activator of transcription 3 activation, resulting in reduced transcription of IL-6 downstream genes. In summary, our study reveals an important role for USP15 in the maintenance of MeCP2 stability and the regulation of IL-6 signaling.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142396480","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":"Substrate preference, RNA binding and active site versatility of Stenotrophomonas maltophilia nuclease SmNuc1, explained by a structural study.","authors":"Kristýna Adámková, Mária Trundová, Tomáš Kovaľ, Blanka Husťáková, Petr Kolenko, Jarmila Dušková, Tereza Skálová, Jan Dohnálek","doi":"10.1111/febs.17265","DOIUrl":"https://doi.org/10.1111/febs.17265","url":null,"abstract":"<p><p>Nucleases of the S1/P1 family have important applications in biotechnology and molecular biology. We have performed structural analyses of SmNuc1 nuclease from Stenotrophomonas maltophilia, including RNA cleavage product binding and mutagenesis in a newly discovered flexible Arg74-motif, involved in substrate binding and product release and likely contributing to the high catalytic rate. The Arg74Gln mutation shifts substrate preference towards RNA. Purine nucleotide binding differs compared to pyrimidines, confirming the plasticity of the active site. The enzyme-product interactions indicate a gradual, stepwise product release. The activity of SmNuc1 towards c-di-GMP in crystal resulted in a distinguished complex with the emerging product 5'-GMP. This enzyme from an opportunistic pathogen relies on specific architecture enabling high performance under broad conditions, attractive for biotechnologies.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142373964","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":"Glycaemic sugar metabolism and the gut microbiota: past, present and future.","authors":"Florine H M Westerbeke, Ilias Attaye, Melany Rios-Morales, Max Nieuwdorp","doi":"10.1111/febs.17293","DOIUrl":"https://doi.org/10.1111/febs.17293","url":null,"abstract":"<p><p>Non-communicable diseases (NCDs), such as type 2 diabetes (T2D) and metabolic dysfunction-associated fatty liver disease, have reached epidemic proportions worldwide. The global increase in dietary sugar consumption, which is largely attributed to the production and widespread use of cheap alternatives such as high-fructose corn syrup, is a major driving factor of NCDs. Therefore, a comprehensive understanding of sugar metabolism and its impact on host health is imperative to rise to the challenge of reducing NCDs. Notably, fructose appears to exert more pronounced deleterious effects than glucose, as hepatic fructose metabolism induces de novo lipogenesis and insulin resistance through distinct mechanisms. Furthermore, recent studies have demonstrated an intricate relationship between sugar metabolism and the small intestinal microbiota (SIM). In contrast to the beneficial role of colonic microbiota in complex carbohydrate metabolism, sugar metabolism by the SIM appears to be less beneficial to the host as it can generate toxic metabolites. These fermentation products can serve as a substrate for fatty acid synthesis, imposing negative health effects on the host. Nevertheless, due to the challenging accessibility of the small intestine, our knowledge of the SIM and its involvement in sugar metabolism remains limited. This review presents an overview of the current knowledge in this field along with implications for future research, ultimately offering potential therapeutic avenues for addressing NCDs.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142368118","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":"RETRACTION: Long Non Coding RNA SLC26A4-AS1 Exerts Antiangiogenic Effects in Human Glioma by Upregulating NPTX1 Via NFKB1 Transcriptional Factor","authors":"","doi":"10.1111/febs.17268","DOIUrl":"10.1111/febs.17268","url":null,"abstract":"<p><b>RETRACTION</b>: H. Li, R. Yan, W. Chen, X. Ding, J. Liu, G. Chen, Q. Zhao, Y. Tang, S. Lv, S. Liu, and Y. Yu, “Long Non Coding RNA SLC26A4-AS1 Exerts Antiangiogenic Effects in Human Glioma by Upregulating NPTX1 Via NFKB1 Transcriptional Factor,” <i>The FEBS Journal</i> 288, no. 1 (2021): 212–228, https://doi.org/10.1111/febs.15325.</p><p>The above article, published online on July 15, 2020, in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief; the Federation of European Biochemical Societies; and John Wiley &amp; Sons Ltd. The retraction has been agreed upon following an investigation into concerns raised by a third party, which revealed inappropriate image duplication between this article (Fig. 1E) and another article previously published elsewhere by a different group of authors in a different scientific context. The authors were unable to provide a satisfactory explanation, and the partial raw data they supplied could not explain the identified issues. Consequently, the editors have lost confidence in the presented data and decided to retract the paper.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/febs.17268","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142335502","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":"Atypical MAPKs in cancer.","authors":"Katrin Dahm, Parthiban Vijayarangakannan, Hans-Peter Wollscheid, Hansjörg Schild, Krishnaraj Rajalingam","doi":"10.1111/febs.17283","DOIUrl":"https://doi.org/10.1111/febs.17283","url":null,"abstract":"<p><p>Impaired kinase signalling leads to various diseases, including cancer. At the same time, kinases make up the majority of the druggable genome and targeting kinase activity has proven to be a successful first-line therapy for many cancers. Among the best-studied kinases are the mitogen-activated protein kinases (MAPKs), which regulate cell proliferation, differentiation, motility, and survival. However, the MAPK family also contains the atypical members ERK3 (MAPK6), ERK4 (MAPK4), ERK7/ERK8 (MAPK15), and NLK that are functionally and structurally different from their conventional family members and have long been neglected. Nevertheless, in recent years, important roles in carcinogenesis, actin cytoskeleton regulation and the immune system have been discovered, underlining the physiological importance of atypical MAPKs and the need to better understand their functions. This review highlights the distinctive features of the atypical MAPKs and summarizes the evidence on their regulation, physiological roles, and potential targeting strategies for cancer therapies.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142335565","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":"Unusual photodynamic characteristics of the light-oxygen-voltage domain of phototropin linked to terrestrial adaptation of Klebsormidium nitens.","authors":"Sunita Sharma, Avinash Kumar Gautam, Rajani Singh, Samudrala Gourinath, Suneel Kateriya","doi":"10.1111/febs.17284","DOIUrl":"https://doi.org/10.1111/febs.17284","url":null,"abstract":"<p><p>Phototropin (Phot), a blue light-sensing LOV domain protein, mediates blue light responses and is evolutionarily conserved across the green lineage. Klebsormidium nitens, a green terrestrial alga, presents a valuable opportunity to study adaptive responses from aquatic to land habitat transitions. We determined the crystal structure of Klebsormidium nitens Phot LOV1 domain (KnLOV1) in the dark and engineered different mutations (R60K, Q122N, and D33N) to modulate the lifetime of the photorecovery cycle. We observed unusual, slow recovery kinetics in the wild-type KnLOV1 domain (τ = 41 ± 3 min) compared to different mutants (R60K: τ = 2.0 ± 0.1 min, Q122N: τ = 1.7 ± 0.1 min, D33N: τ = 9.6 ± 0.1 min). Crystal structures of wild-type KnLOV1 and mutants revealed subtle but critical changes near the protein chromophore that is responsible for modulating protein dark recovery time. Our findings shed light on the unique structural and biochemical characteristics of the newly studied KnLOV1 and its evolutionary importance for phototropin-mediated physiology.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142335506","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":"Crystal structure of Alzheimer's disease phospholipase D3 provides a molecular basis for understanding its normal and pathological functions.","authors":"Kenta Ishii, Stefan J Hermans, Maria Eleni Georgopoulou, Tracy L Nero, Nancy C Hancock, Gabriela A N Crespi, Michael A Gorman, Jonathan H Gooi, Michael W Parker","doi":"10.1111/febs.17277","DOIUrl":"https://doi.org/10.1111/febs.17277","url":null,"abstract":"<p><p>Human 5'-3' exonuclease PLD3, a member of the phospholipase D family of enzymes, has been validated as a therapeutic target for treating Alzheimer's disease. Here, we have determined the crystal structure of the luminal domain of the enzyme at 2.3 Å resolution, revealing a bilobal structure with a catalytic site located between the lobes. We then compared the structure with published crystal structures of other human PLD family members which revealed that a number of catalytic and lipid recognition residues, previously shown to be key for phospholipase activity, are not conserved or, are absent. This led us to test whether the enzyme is actually a phospholipase. We could not measure any phospholipase activity but the enzyme shows robust nuclease activity. Finally, we have mapped key single nucleotide polymorphisms onto the structure which reveals plausible reasons as to why they have an impact on Alzheimer's disease.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142335501","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}