The FEBS journal最新文献_第3页

Distinct interaction modes orchestrate the polymerization of ASC PYD and CARD domains into filamentous structures. 不同的相互作用模式协调ASC、PYD和CARD结构域聚合成丝状结构。

IF 4.2

The FEBS journal Pub Date : 2025-08-28 DOI: 10.1111/febs.70242

Hasan Ozan Otas, Nesrin Erkol

{"title":"Distinct interaction modes orchestrate the polymerization of ASC PYD and CARD domains into filamentous structures.","authors":"Hasan Ozan Otas, Nesrin Erkol","doi":"10.1111/febs.70242","DOIUrl":"https://doi.org/10.1111/febs.70242","url":null,"abstract":"Apoptosis-associated speck-like protein containing a CARD (ASC) is an adaptor protein composed of a pyrin domain (PYD) and a caspase activation and recruitment domain (CARD). ASC plays a key role in the inflammasome complex by forming a supramolecular structure called the ASC speck, which promotes inflammation and pyroptosis. The assembly of ASC-dependent inflammasomes is mediated by homotypic interactions between receptor, adaptor, and effector proteins, with PYD-PYD and CARD-CARD interactions categorized into three major types (type I, II, and III). These interactions orchestrate the homo-oligomerization of inflammasome components, serving as a platform for caspase-1 activation. Through maintaining interaction homeostasis, ASC regulates innate immune responses and functions as a tumor suppressor. Dysregulation of ASC due to genetic mutations is implicated in various cancers and autoimmune diseases. However, the mechanisms driving ASC speck formation remain unclear, leaving questions on its domain-specific interactions. To address this, we used a cell line model to investigate the roles of single and double mutations within the PYD and CARD domains of ASC. We separately fused wild-type (wt)PYD and wtCARD domains to GFP and mCherry to assess the effects of these mutations on interaction dynamics using fluorescence microscopy and Förster resonance energy transfer (FRET) systems. Our results reveal previously unknown cooperative mechanisms in which specific PYD and CARD residues function as enhancers or disruptors of homo-oligomerization, highlighting the importance of cumulative interaction effects. Our study provides new insights into the molecular basis of ASC domain polymerizations.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144984426","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}

引用次数: 0

Newly identified properties of known pharmaceuticals and myxobacterial small molecules revealed by screening for autophagy modulators. 通过筛选自噬调节剂揭示了已知药物和黏菌小分子的新特性。

IF 4.2

The FEBS journal Pub Date : 2025-08-28 DOI: 10.1111/febs.70243

Janine Fichtner, Yan Yan Beer, H G Mauricio Ramm, Sabrina Mühlen, Frank Surup, Jennifer Herrmann, Toni Luise Meister, Stephanie Pfaender, Ursula Bilitewski, Mark Brönstrup, Rolf Müller, Manfred Wirth, Eeva-Liisa Eskelinen, Ingo Schmitz

{"title":"Newly identified properties of known pharmaceuticals and myxobacterial small molecules revealed by screening for autophagy modulators.","authors":"Janine Fichtner, Yan Yan Beer, H G Mauricio Ramm, Sabrina Mühlen, Frank Surup, Jennifer Herrmann, Toni Luise Meister, Stephanie Pfaender, Ursula Bilitewski, Mark Brönstrup, Rolf Müller, Manfred Wirth, Eeva-Liisa Eskelinen, Ingo Schmitz","doi":"10.1111/febs.70243","DOIUrl":"https://doi.org/10.1111/febs.70243","url":null,"abstract":"Autophagy is a cellular degradation and recycling process important for maintaining cellular health and function. It is constitutively active at a low level in eukaryotic cells and can be induced by conditions of cellular stress, such as nutrient starvation. Moreover, autophagy plays an important role in diverse processes such as immunobiology, pathogen infection, ageing, and neurodegenerative and other diseases. Using a high-content fluorescence assay for microtubule-associated protein 1 light chain 3 beta (LC3B), a major player in the autophagic pathway, we screened a library of commercial drugs and natural products for activators and inhibitors of LC3B-positive vesicle accumulation. Positive hits for known autophagy modulators included anisomycin, amphotericin B, carbonyl cyanide m-chlorophenylhydrazone (CCCP) and cytochalasin D. Importantly, we identified several new autophagy modulators, such as aciclovir and myxobacterial vioprolides. Anisomycin, aciclovir and vioprolides promoted intracellular growth of Staphylococcus aureus, a bacterium that is known to be a target of autophagy. In contrast, anisomycin strongly inhibited influenza A virus and SARS-CoV-2 replication. Subsequently, we investigated the influence of these autophagy modulators in a cellular disease model of neuronal vacuolation and spinocerebellar degeneration (NVSD), which is associated with cysteine protease ATG4D mutations. We provide evidence that anisomycin and famciclovir, an aciclovir analogue, can normalise the elevated amount of LC3-positive vesicles in mutant fibroblasts, highlighting their potential for the treatment of NVSD. Thus, the screening method enabled the identification of autophagy-modulating compounds with therapeutic potential.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144984575","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}

引用次数: 0

Combating muscle atrophy: emerging therapeutic targets that are fiber-type-specific. 对抗肌肉萎缩：纤维类型特异性的新兴治疗靶点。

IF 4.2

The FEBS journal Pub Date : 2025-08-28 DOI: 10.1111/febs.70241

Samrat Chakraborty, Raz Ben-David, Shenhav Shemer

引用次数: 0

Lysine demethylase 4A is a centrosome-associated protein required for centrosome integrity and genomic stability. 赖氨酸去甲基酶4A是中心体完整性和基因组稳定性所必需的中心体相关蛋白。

IF 4.2

The FEBS journal Pub Date : 2025-08-28 DOI: 10.1111/febs.70240

Pratim Chowdhury, Xiaoli Wang, Richard I Han, Manga Motrapu, Ashley G Boice, Yuya Nakatani, Sofia Vargas-Hernandez, Julia F Love, Claude Chew, Sandra L Grimm, Dereck Mezquita, Frank M Mason, Elisabeth D Martinez, Cristian Coarfa, Cheryl L Walker, Anna-Karin Gustavsson, Ruhee Dere

{"title":"Lysine demethylase 4A is a centrosome-associated protein required for centrosome integrity and genomic stability.","authors":"Pratim Chowdhury, Xiaoli Wang, Richard I Han, Manga Motrapu, Ashley G Boice, Yuya Nakatani, Sofia Vargas-Hernandez, Julia F Love, Claude Chew, Sandra L Grimm, Dereck Mezquita, Frank M Mason, Elisabeth D Martinez, Cristian Coarfa, Cheryl L Walker, Anna-Karin Gustavsson, Ruhee Dere","doi":"10.1111/febs.70240","DOIUrl":"10.1111/febs.70240","url":null,"abstract":"Centrosomes play a fundamental role in nucleating and organizing microtubules in the cell and are vital for faithful chromosome segregation and maintenance of genomic stability. Loss of structural or functional integrity of centrosomes causes genomic instability and is a driver of oncogenesis. Here we identify lysine demethylase 4A (KDM4A), an epigenetic 'eraser' of chromatin methyl marks, as a centrosome-localized protein, visualized at the nanometer-scale resolution. We additionally uncovered that KDM4A demethylase enzymatic activity is required to maintain centrosome homeostasis and integrity; a previously unknown functionality unlinked to altered expression of genes regulating centrosome number. We find that KDM4A interacts with and localizes to the centrosome in all stages of mitosis, where it maintains centrosome numbers and centriole engagement during mitosis. Loss of KDM4A results in supernumerary centrosomes and accrual of chromosome segregation errors including chromatin bridges and micronuclei, markers of genomic instability. In summary, these data highlight a previously unknown role for an epigenetic 'eraser' regulating centrosome integrity, mitotic fidelity, and genomic stability at the centrosome.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144984516","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}

引用次数: 0

Research highlights: Hidden gems. 研究亮点：隐藏的宝石。

IF 4.2

The FEBS journal Pub Date : 2025-08-25 DOI: 10.1111/febs.70225

Hajrah Khawaja

引用次数: 0

CDKL5 regulates the initiation of retrograde axonal transport through CLIP170-dynactin complex formation. CDKL5通过CLIP170-dynactin复合物的形成调控轴突逆行转运的启动。

IF 4.2

The FEBS journal Pub Date : 2025-08-23 DOI: 10.1111/febs.70230

Serena Baldin, Clara Carmone, Giorgia Valetti, Roberta De Rosa, Isabella Barbiero

{"title":"CDKL5 regulates the initiation of retrograde axonal transport through CLIP170-dynactin complex formation.","authors":"Serena Baldin, Clara Carmone, Giorgia Valetti, Roberta De Rosa, Isabella Barbiero","doi":"10.1111/febs.70230","DOIUrl":"https://doi.org/10.1111/febs.70230","url":null,"abstract":"Cyclin-dependent kinase-like 5 (CDKL5) is a serine-threonine kinase implicated in regulating microtubule (MT) dynamics. Mutations in CDKL5 are associated with a rare neurodevelopmental disease called CDKL5 deficiency disorder (CDD), which is characterized by early-onset seizures and intellectual disabilities. Microtubule (MT)-related functions of CDKL5 are in part correlated with its interaction with MT-associated proteins, such as CAP-Gly domain-containing linker protein 1 [CLIP1; also known as cytoplasmic linker protein 170 alpha-2 (CLIP170)]. CLIP170 is a MT plus-end tracking protein that, once activated, can bind MTs and other proteins, favoring MT dynamics. Importantly, we have previously shown that CLIP170 is inactive in the absence of CDKL5, thus hindering MT functions. One of the best-characterized interactors of CLIP170 is dynactin, a multisubunit complex that binds the motor protein dynein. In particular, in neurons, active CLIP170 localizes to MTs in the axonal periphery, where it serves as a docking site for the interaction with dynactin, which in turn recruits dynein and various cargos, favoring the initiation of retrograde transport toward the neuronal soma. Here, we demonstrated that CLIP170-dynactin complex formation is impaired in the absence of CDKL5, thus leading to defective retrograde cargo trafficking. Overall, our findings expand the knowledge on the molecular mechanisms underlying neuronal transport and provide novel information regarding the etiopathogenesis of CDD.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144984467","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}

引用次数: 0

Development of a highly active engineered PETase enzyme for polyester degradation. 聚酯降解高活性工程酶的研制。

IF 4.2

The FEBS journal Pub Date : 2025-08-23 DOI: 10.1111/febs.70228

Shapla Bhattacharya, Rossella Castagna, Hajar Estiri, Toms Upmanis, Andrea Ricci, Alfonso Gautieri, Emilio Parisini

{"title":"Development of a highly active engineered PETase enzyme for polyester degradation.","authors":"Shapla Bhattacharya, Rossella Castagna, Hajar Estiri, Toms Upmanis, Andrea Ricci, Alfonso Gautieri, Emilio Parisini","doi":"10.1111/febs.70228","DOIUrl":"https://doi.org/10.1111/febs.70228","url":null,"abstract":"Polyethylene terephthalate (PET) accounts for ≈6% of global plastic production, contributing considerably to the global solid-waste stream and environmental plastic pollution. Since the discovery of PET-depolymerizing enzymes, enzymatic PET recycling has been regarded as a promising method for plastic disposal, particularly in the context of a circular economy strategy. However, because the PET-degrading enzymes developed so far suffer from relatively limited thermostability and low catalytic efficiency, as well as degradation product inhibition, their large-scale industrial applications are still largely hampered. To overcome these limitations, we engineered the current PET-hydrolyzing enzyme gold standard [the ICCG variant of leaf-branch compost cutinase (LCC-ICCG)] using in silico protein design methods to develop a PET-hydrolyzing enzyme that features enhanced thermal stability and PET depolymerization activity. Our mutant, LCC-ICCG-C09, features a 3.5 °C increase in melting temperature relative to the LCC-ICCG enzyme. Under optimal reaction conditions (68 °C), the engineered enzyme hydrolyzes amorphous PET material into terephthalic acid (TPA) with a two-fold higher efficiency compared to LCC-ICCG. Owing to its enhanced properties, LCC-ICCG-C09 may be a promising candidate for future applications in industrial PET recycling processes.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144984494","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}

引用次数: 0

CLEC18A interacts with sulfated glycosaminoglycans and controls clear cell renal cell carcinoma progression. CLEC18A与硫代糖胺聚糖相互作用并控制透明细胞肾细胞癌的进展。

IF 4.2

The FEBS journal Pub Date : 2025-08-23 DOI: 10.1111/febs.70236

Gustav Jonsson, Maura Hofmann, Stefan Mereiter, Lauren Hartley-Tassell, Masahiro Onji, Irma Sakic, Tiago Oliveira, David Hoffmann, Maria Novatchkova, Alexander Schleiffer, Josef M Penninger

{"title":"CLEC18A interacts with sulfated glycosaminoglycans and controls clear cell renal cell carcinoma progression.","authors":"Gustav Jonsson, Maura Hofmann, Stefan Mereiter, Lauren Hartley-Tassell, Masahiro Onji, Irma Sakic, Tiago Oliveira, David Hoffmann, Maria Novatchkova, Alexander Schleiffer, Josef M Penninger","doi":"10.1111/febs.70236","DOIUrl":"https://doi.org/10.1111/febs.70236","url":null,"abstract":"C-type lectins are a large protein family with essential functions in both health and disease. In cancer, some C-type lectins have been found to both promote and inhibit tumor growth, but many of the C-type lectins still remain uncharacterized. Here, we report a key role of the C-type lectin domain family 18 members (CLEC18 family) in the progression of clear cell renal cell carcinoma (ccRCC). The CLEC18 family is conserved across the entire Chordata phylum, with a high frequency of duplication events in humans compared to other species. We found that CLEC18A is exclusively expressed in the proximal tubule of the kidney and the medial habenula of the brain. We further identified sulfated glycosaminoglycans as the main CLEC18A ligand, making them unique among C-type lectins. In ccRCC patients, high expression of genes in the CLEC18 family in the tumor is associated with improved survival. In mouse models of ccRCC, deletion of the mouse ortholog, Clec18a, resulted in enhanced tumor growth. Our results establish CLEC18A as a newly identified and critical regulator of ccRCC tumor growth and highlight the potential benefit of modulating expression of CLEC18 family genes in the renal tumor microenvironment.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144984513","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}

引用次数: 0

Mechanism of cyanobacterial ferredoxin-dependent flavin thioredoxin reductase reveals thiolate-FAD charge transfer and catalytic asymmetry in a homodimer. 蓝藻铁氧化还蛋白依赖黄素硫氧还蛋白还原酶的机制揭示了硫酸盐- fad电荷转移和同型二聚体中的催化不对称。

IF 4.2

The FEBS journal Pub Date : 2025-08-23 DOI: 10.1111/febs.70210

Martha Minjarez-Saenz, Víctor Correa-Pérez, Maribel Rivero, Alejandro Hernández-Gómez, Marta Martínez-Júlvez, Rubén M Buey, Federico Gago, Monica Balsera, Milagros Medina

{"title":"Mechanism of cyanobacterial ferredoxin-dependent flavin thioredoxin reductase reveals thiolate-FAD charge transfer and catalytic asymmetry in a homodimer.","authors":"Martha Minjarez-Saenz, Víctor Correa-Pérez, Maribel Rivero, Alejandro Hernández-Gómez, Marta Martínez-Júlvez, Rubén M Buey, Federico Gago, Monica Balsera, Milagros Medina","doi":"10.1111/febs.70210","DOIUrl":"https://doi.org/10.1111/febs.70210","url":null,"abstract":"Ferredoxin-dependent flavin thioredoxin reductases (FFTRs) catalyze the reduction of the disulfide bond in thioredoxins using electrons transferred from ferredoxin, and therefore play a pivotal role in cellular disulfide relay reactions. FFTRs are essential in cyanobacteria such as Gloeobacter and Prochlorococcus, in which they serve as the sole thioredoxin reduction system, as well as in certain Clostridium species, where they are implicated in processes such as sporulation. Despite the well-established role of ferredoxin in reducing FFTRs, the underlying mechanistic details remain poorly understood. This study examines the catalytic cycle of FFTR from Gloeobacter violaceus, focusing on the role of its redox-active disulfide in electron transfer. We demonstrate that FFTR has a highly negative flavin adenine dinucleotide (FAD) midpoint reduction potential, which explains its preference for ferredoxin over nicotinamide adenine dinucleotide phosphate (NADPH) as an electron source. Spectroscopic detection of a thiolate-flavin charge transfer complex along the enzyme reduction pathway provides the first experimental evidence of a previously elusive FFTR catalytic conformation. Our results further reveal sequential FAD reduction within the enzyme homodimer that strongly suggests monomer asymmetry. Moreover, the impaired flavin reduction observed in an enzyme variant lacking the disulfide highlights the essential role of this redox group in efficient electron transfer. These findings deepen our understanding of FFTR's unique functional adaptations and evolutionary significance. More broadly, they provide a framework for exploring similar electron transfer mechanisms in other flavoproteins with a view to expanding our understanding of their redox biochemistry.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144984560","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}

引用次数: 0

Competition between binding partners of yeast Pex3 affects peroxisome biology. 酵母Pex3结合伙伴之间的竞争影响过氧化物酶体的生物学。

IF 4.2

The FEBS journal Pub Date : 2025-08-23 DOI: 10.1111/febs.70229

Eline M F de Lange, Grzegorz Chojnowski, Jérôme Bürgi, Rifka Vlijm, Matthias Wilmanns, Ida J van der Klei

{"title":"Competition between binding partners of yeast Pex3 affects peroxisome biology.","authors":"Eline M F de Lange, Grzegorz Chojnowski, Jérôme Bürgi, Rifka Vlijm, Matthias Wilmanns, Ida J van der Klei","doi":"10.1111/febs.70229","DOIUrl":"https://doi.org/10.1111/febs.70229","url":null,"abstract":"Peroxisomes are important membrane-bound organelles that are involved in a multitude of metabolic processes. Peroxisomal biogenesis factor 3 (Pex3) is a crucial peroxisomal membrane protein (PMP) that plays a vital role in many of these processes through the specific recruitment of several binding partners. In the yeast Hansenula polymorpha, Pex3 recruits PMP import receptor Pex19, the receptor for newly synthesized PMPs; autophagy-related protein 30 (Atg30), a protein involved in the selective breakdown of peroxisomes (pexophagy); and inheritance of peroxisomes protein 1 (Inp1), a protein important for peroxisome retention in mother cells. Here, we show that the overexpression of any of these proteins affects peroxisomal processes, with the level of overexpression being the primary determinant of competition. This finding is confirmed by our analysis based on the crystal structure model of the H. polymorpha Pex3-Pex19 complex and AlphaFold2 predictions. It shows that the interaction regions of Pex3 with these proteins overlap. These results provide a crucial insight into the complex role of Pex3 in regulating different processes in peroxisome biology.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144984436","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}

引用次数: 0