The FEBS journal最新文献

{"title":"Rational design of Chim3, a multifunctional peptide carrying a formyl peptide receptor 2 (FPR2) agonist module released by bacterial signal peptidase I (Spase I).","authors":"Samuel R Costa, Bianca O Lira, Gabriel F G Calixto, João B Nunes, Sabrina A Machado, Andreanne G Vasconcelos, Ana L P Lourenço, Thaís C de Sousa, Sónia Gonçalves, André M Murad, Nuno C Santos, José R de S de Almeida Leite, Kelly G Magalhães, Marcelo S Ramada, Guilherme D Brand","doi":"10.1111/febs.70055","DOIUrl":"https://doi.org/10.1111/febs.70055","url":null,"abstract":"<p><p>Membrane-active peptides are useful tools in the design of multifunctional molecules. For example, peptide chimeras may release, after proteolysis of membrane-adsorbed molecules, pharmacologically active fragments. In previous work, Chim2, an antimicrobial peptide composed of a membrane-active module, an enzymatic hydrolysis site, and an agonist moiety for type 2 formyl peptide receptors (FPR2), was conceptualized. Based on Chim2, a peptide named Chim3 was designed, adding a consensus sequence for the bacterial signal peptidase I (Spase I). Spase I is a protease located in an extracytoplasmic face of Gram-positive and Gram-negative bacterial membranes and is essential for protein export. Chim3 was synthesized and its activity as an antimicrobial agent was determined. In addition, Chim3 was incubated with Escherichia coli and Staphylococcus aureus, and peptide hydrolysis products were evaluated by LC-MS/MS. Data demonstrate that Chim3 has potent antimicrobial activity. After incubation with bacteria, Chim3 underwent intense hydrolysis. Proteolysis was detected in the Chim3 Spase I consensus sequence after incubation with both bacteria, and the release of the FPR2 agonist segment was observed. The synthesis of an improved structure of Chim3 with N-methyl tyrosine in the FPR2 agonist segment was performed, resulting in CHIM3Y-NMe. This modification caused significantly higher concentrations of the FPR2 agonist portion arising from the modified peptide after incubation assays with E. coli. The modified FPR2 agonist WK(Y-NMe)M-NH₂ interacted with the mouth region of FPR2 and induced the release of TNF-α and IL-6 in mouse macrophages, making CHIM3Y-NMe an interesting antimicrobial and immunomodulatory molecule for further development aimed at in vivo application.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607183","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":"A steric gate prevents mutagenic dATP incorporation opposite 8-oxo-deoxyguanosine in mitochondrial DNA polymerases.","authors":"Noe Baruch-Torres, Carlos H Trasviña-Arenas, Alexandru Ionut Gilea, Upeksha C Dissanayake, Missael Molina-Jiménez, Paola L García-Medel, Corina Díaz-Quezada, Tiziana Lodi, G Andrés Cisneros, Enrico Baruffini, Luis G Brieba","doi":"10.1111/febs.70064","DOIUrl":"https://doi.org/10.1111/febs.70064","url":null,"abstract":"<p><p>Reactive oxygen species (ROS) generate DNA lesions that alter genome integrity. Among those DNA lesions, 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxodG) is particularly mutagenic. 8-oxodG efficiently incorporates deoxycytidine monophosphate (dCMP) and deoxyadenosine monophosphate (dAMP) via base pairing mediated by its anti and syn conformations, respectively. In family-A DNA polymerases (DNAPs), the amino acids responsible for modulating dCMP or dAMP incorporation across 8-oxodG are located in a determined structural position. Those residues are a conserved tyrosine located at the N terminus of the α-helix O and a nonconserved residue located six amino acids after this conserved tyrosine. In yeast mitochondrial DNAP (DNA-directed DNA polymerase gamma MIP1 [Mip1]), those residues correspond to amino acids Y757 and F763. We hypothesized that the phenyl group of the F763 residue impinges on the syn conformation of 8-oxodG, therefore reducing dAMP misincorporation. Here, we measured dCMP and dAMP incorporation across 8-oxodG using wild-type and F763 Mip1 mutants. Our data suggest that both residue F763 and the universally conserved Y757 assemble a steric gate that obtrudes the 8-oxodG(syn) conformation. As the human orthologue of Mip1, DNA polymerase gamma (HsPolγ) or DNAP γ, also harbors phenylalanine at the corresponding position to Mip1-F763, the steric gate mechanism might similarly be responsible for controlling HsPolγ's fidelity when tolerating 8-oxodG lesions.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607219","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":"Caspase-1/11 controls Zika virus replication in astrocytes by inhibiting glycolytic metabolism.","authors":"Ingrid S de Farias, Guilherme Ribeiro, Isaú H Noronha, Victoria Weise L Lucena, Jean P S Peron, Pedro M Moraes-Vieira, Jose C Alves-Filho, Karina R Bortoluci","doi":"10.1111/febs.70061","DOIUrl":"https://doi.org/10.1111/febs.70061","url":null,"abstract":"<p><p>Zika virus (ZIKV) poses a significant threat due to its association with severe neurological complications, particularly during pregnancy. Although viruses exhibit tropism for neural cells, including astrocytes, the role of these cells in controlling ZIKV replication remains unclear. In this study, we demonstrated that ZIKV induces caspase-1 activation in primary astrocytes despite the absence of classical signs of inflammasome activation. Caspase-1 and caspase-11 double knockout (caspase-1/11^-/-) astrocytes exhibit heightened permissiveness to viral replication, accompanied by overactivation of glycolytic metabolism. Inhibition of glycolysis reversed the susceptibility of caspase-1/11^-/- astrocytes to ZIKV infection. Protein network analysis revealed mammalian target of rapamycin complex (mTORC) as a link between proteins involved in glycolysis and caspase-1, and mTORC inhibition also suppressed viral replication. Furthermore, we found that the impact of caspase-1/11 on astrocytes depends on the regulation of pyruvate transport to mitochondria for viral replication. Overall, our findings elucidate a caspase-1/11-dependent microbicidal mechanism in astrocytes that involves the mTORC/glycolytic pathway/pyruvate axis, providing insights into potential therapeutic targets for ZIKV infection.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607221","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":"The deubiquitinase inhibitor WP1130 drives nuclear aggregation and reactivation of mutant p53 for selective cancer cell targeting.","authors":"Swapnil Oak, Onkar Karajgikar, Nikhil Gadewal, Prasad Sulkshane, Tripti Verma, Sanjay Gupta, Tanuja Teni","doi":"10.1111/febs.70036","DOIUrl":"https://doi.org/10.1111/febs.70036","url":null,"abstract":"<p><p>Mutations in the TP53 gene may lead to the loss of its tumor suppressor function and the acquisition of oncogenic properties. The enhanced stability of mutant p53 (mutp53) is one of the pivotal factors for its oncogenic functions, rendering proteins implicated in mutp53 stabilization as promising targets for therapeutic intervention. Although deubiquitinases (DUBs) are commonly deregulated in various cancers, their specific impact on mutp53 stabilization remains largely unexplored. In this study, we demonstrated the involvement of DUBs-USP5 and USP9X in-enhancing mutp53 stability while revealing the effects of DUB inhibitor WP1130 in selectively destabilizing different p53 mutants in cancer cells of various origins. Mechanistically, WP1130 induced mutp53 ubiquitination and nuclear aggregation, resulting in its partitioning to the detergent-insoluble fraction. Moreover, combined treatment with the proteasome inhibitor augmented mutp53 accumulation in this fraction, indicating proteasomal degradation of these aggregates. Interestingly, WP1130 did not alter the stability or induce aggregation of WTp53 protein, suggesting its selective targeting of mutp53. Furthermore, WP1130 disrupted the interaction of mutp53 with HSP40 and HSP90 while promoting its association with ubiquitin ligase CHIP, thereby facilitating mutp53 destabilization. Notably, WP1130 reactivated mutp53 via induction of a wild-type-like p53 conformation, upregulating its downstream effectors and inducing apoptosis, possibly due to its targeted binding near the mutation site, as suggested by our in silico analysis. These findings highlight the roles of USP9X and USP5 in mutp53 stabilization and underscore the therapeutic potential of DUB inhibitor WP1130 for the selective targeting of mutp53-expressing cancer cells.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607184","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":"Derivatives of MOPS: promising scaffolds for SARS coronaviruses Macro domain-targeted inhibition.","authors":"Oney Ortega Granda, Karine Alvarez, Benjamin Morin, Bruno Canard, François Ferron, Nadia Rabah","doi":"10.1111/febs.70039","DOIUrl":"https://doi.org/10.1111/febs.70039","url":null,"abstract":"<p><p>The severe acute respiratory syndrome coronavirus (SARS-CoV/CoV-2) genome encodes 16 non-structural proteins (nsps), which coordinate cell remodeling, virus replication and participate in viral evasion. Notably, nsp3 contains a protein module termed Macro domain, which carries IFN antagonist activity that interferes with host innate immunity response. This domain is able to bind and hydrolyze ADP-ribose derivatives. This activity is correlated to viral escape and thus makes Macro domains a valuable therapeutic target. In the present paper, we report a SARS-CoV Macro domain structure in complex with a MOPS molecule. Based on our structural data, molecular docking was performed on a set of MOPS analogs in the ADP-ribose binding pocket. We present an ELISA-based assay to select hits based on the inhibition of recombinant SARS-CoV/CoV-2 Macro domain-ADP-ribose complex formation. Among the tested analogs, MOPSO and CAPSO are the more efficient in inhibiting ADP-ribose-binding. Structural analysis of these molecules in the ADP-ribose pocket reveals potential interactions with amino acid residues involved in the coordination of ADP-ribose. Overall, these findings suggest that MOPSO and CAPSO bear potential to be used as a scaffold for the design of Macro domain-specific inhibitors.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607181","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":"When the host senses the microbiota's metabolism - the interplay between food and microbiota in C. elegans.","authors":"José Eduardo Gomes","doi":"10.1111/febs.70054","DOIUrl":"https://doi.org/10.1111/febs.70054","url":null,"abstract":"<p><p>The microbiota plays a major role in metazoan physiology, particularly in the intestinal tract. Nonetheless, its extreme complexity hinders functional studies. Taking advantage of the Caenorhabditis elegans and Escherichia coli model systems, Feng et al. report the physiological effect of purine biosynthesis deficiencies in E. coli-the microbiota in this experimental system-on C. elegans. Mutant E. coli bacteria, particularly those harboring mutations in the purE gene, trigger a stress response in C. elegans. The E. coli purE mutant is defective for the enzyme N⁵-carboxyaminoimidazole ribonucleotide mutase (N⁵-CAIR), suggesting that this intermediate metabolite may play a central role in this microbiota-host interaction.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589141","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":"Protometabolic functions of pyridoxal: A link between early amino acid synthesis and enzyme evolution.","authors":"Mariarita Bertoldi, Gianluca Molla","doi":"10.1111/febs.70056","DOIUrl":"https://doi.org/10.1111/febs.70056","url":null,"abstract":"<p><p>In the framework of studies on protometabolism, Schlikker et al. characterized the conversion of pyridoxal to pyridoxamine under conditions mimicking the ones likely existing at the origin of metabolism. These conditions triggered nitrogen incorporation into amino acids in solution before the origins of enzymes. The suggested role for pyridoxal highlights its pivotal function in the transition from inorganic ammonia-dependent amino acid synthesis to organic reactions in aqueous solution and supports the \"metabolism first\" theory for biological evolution. Insights from the early evolution of natural enzymes can inspire the development of novel biocatalysts for biotechnological applications based on the catalytic versatility of pyridoxal.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143576081","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":"Exosites: beyond the limitations of the protease active site.","authors":"Gonzalo Izaguirre","doi":"10.1111/febs.70057","DOIUrl":"https://doi.org/10.1111/febs.70057","url":null,"abstract":"<p><p>Proteases rely on their active sites for substrate specificity, but these sites have inherent limitations that impact enzymatic efficiency and regulation. Exosites and cofactors help overcome these constraints by enhancing the protease's substrate interactions, specificity, and inhibition. Recent research by Gangemi et al. highlights the role of exosites in regulating the inhibition of the protease neutrophil elastase by the serpin alpha-1-antitrypsin. Understanding these mechanisms is crucial for developing therapeutic applications. Advances in computational analysis provide new insights into exosite function, complementing traditional structural studies and expanding potential biotechnological applications of protease inhibitors.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143574940","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":"A PDE4 shortform degrader: a first in isoform-specific PDE4 inhibition.","authors":"Donald H Maurice","doi":"10.1111/febs.70059","DOIUrl":"https://doi.org/10.1111/febs.70059","url":null,"abstract":"<p><p>Although phosphodiesterase 4 (PDE4) inhibitors have reached the clinic, their lack of selectivity for PDE4 enzyme isoforms leads to documented side effects. Building in enzyme selectivity has proved difficult because all PDE4 enzymes share highly conserved catalytic domains. The report by Sin et al. describes a novel approach in which a potent PDE4 proteolysis targeting chimera (PROTAC) selectively promotes the degradation of a small subset of PDE4 isoforms (i.e., \"short forms\") and impacts inflammatory events regulated by these enzymes. This approach offers unparalleled selectivity, potency, and could represent the dawn of a new pharmacology for selective regulation of cyclic AMP (cAMP) signaling.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143574938","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 novel alpha isoform of the long-known enzyme LDHA provides new insights into cancer research.","authors":"Wonyoung Park, Shibo Wei, Dongryeol Ryu, Ki-Tae Ha","doi":"10.1111/febs.70058","DOIUrl":"https://doi.org/10.1111/febs.70058","url":null,"abstract":"<p><p>Lactate dehydrogenase A is a key enzyme in energy metabolism, with significant roles in cancer progression. Huang et al. identified LDHAα, a novel LDHA isoform derived from an alternative transcript initiated at AUG198, producing a protein 3 kDa larger than canonical LDHA. LDHAα exhibits enhanced glycolytic activity and promotes glucose uptake, lactate production, and tumor growth more effectively than LDHA. Regulated by c-MYC and FOXM1, LDHAα is mainly cytoplasmic and serves as a potential cancer biomarker and therapeutic target. These findings highlight LDHAα's unique role in cancer metabolism and its potential for advancing targeted cancer therapies.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569304","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}