The FEBS journal最新文献_第2页

Structural characterisation of nucleotide sugar short-chain dehydrogenases/reductases from the thermophilic pseudomurein-containing methanogen Methanothermobacter thermautotrophicus ΔH. 含假尿素的嗜热产甲烷菌（Methanothermobacter thermautotrophicus ΔH）核苷酸糖短链脱氢酶/还原酶的结构特征。

IF 4.2

The FEBS journal Pub Date : 2025-09-03 DOI: 10.1111/febs.70248

Vincenzo Carbone, Linley R Schofield, Patrick J B Edwards, Andrew J Sutherland-Smith, Ron S Ronimus

{"title":"Structural characterisation of nucleotide sugar short-chain dehydrogenases/reductases from the thermophilic pseudomurein-containing methanogen Methanothermobacter thermautotrophicus ΔH.","authors":"Vincenzo Carbone, Linley R Schofield, Patrick J B Edwards, Andrew J Sutherland-Smith, Ron S Ronimus","doi":"10.1111/febs.70248","DOIUrl":"https://doi.org/10.1111/febs.70248","url":null,"abstract":"Epimerases and dehydratases are widely studied members of the extended short-chain dehydrogenase/reductase (SDR) enzyme superfamily and are important in nucleotide sugar conversion and diversification, for example, the interconversion of uridine diphosphate (UDP)-linked glucose and galactose. Methanothermobacter thermautotrophicus contains a cluster of genes, the annotations of which indicate involvement in glycan biosynthesis such as that of cell walls or capsular polysaccharides. In particular, genes encoding UDP-glucose 4-epimerase related protein (Mth375), UDP-glucose 4-epimerase homologue (Mth380) and dTDP-glucose 4,6-dehydratase related protein (Mth373) may be involved in the biosynthesis of an unusual aminosugar in pseudomurein. In this paper, we present the structures of Mth375, an archaeal sugar epimerase/dehydratase protein (WbmF) determined to a resolution of 2.0 Å. The structure contains an N-terminal Rossmann-fold domain with bound nicotinamide adenine dinucleotide hydride (NADH) and a C-terminal catalytic domain with bound UDP. We also present the structure for Mth373 co-crystallised with uridine-5'-diphosphate-xylopyranose to a resolution of 1.96 Å as a NAD+-dependent oxidative decarboxylase (UDP-xylose synthase; EC4.1.1.35). Molecular modelling has also allowed for the identification of Mth380 as a UDP-N-acetylglucosamine 4-epimerase (WbpP; EC5.1.3.7), Mth631 as a UDP-glucose 4-epimerase (GalE; EC5.1.3.2) and Mth1789 as a classical dTDP-d-glucose 4,6-dehydratase (EC4.2.1.46). The UDP-sugar specificity of each archaeal nucleotide sugar short-chain dehydrogenase/reductase (NS-SDR) was elucidated via sequence, molecular modelling and structural analyses. Overall, these structures potentially shed light on the formation of the glycan portion of pseudomurein and capsular polysaccharide in Archaea.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995010","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

Structural insights into how vacuolar sorting receptor recognizes the C-terminal sorting determinant of a vicilin-like seed storage protein. 液泡分选受体如何识别维西林样种子储存蛋白的c端分选决定因素的结构见解。

IF 4.2

The FEBS journal Pub Date : 2025-09-02 DOI: 10.1111/febs.70245

Shu Nga Lui, Hsi-En Tsao, Anthony Hiu-Fung Lo, Liwen Jiang, Kam-Bo Wong

{"title":"Structural insights into how vacuolar sorting receptor recognizes the C-terminal sorting determinant of a vicilin-like seed storage protein.","authors":"Shu Nga Lui, Hsi-En Tsao, Anthony Hiu-Fung Lo, Liwen Jiang, Kam-Bo Wong","doi":"10.1111/febs.70245","DOIUrl":"https://doi.org/10.1111/febs.70245","url":null,"abstract":"During seed development, vacuolar sorting receptors (VSRs) recognize a sequence-specific vacuolar sorting determinant located at the C terminus (ctVSD) of storage proteins, thereby sorting them into protein storage vacuoles. The protease-associated (PA) domain of VSRs is responsible for interacting with the ctVSD of cargo proteins. Here, we report the crystal structure of the PA domain of Arabidopsis vacuolar-sorting receptor 1 (VSR1) in complex with the C-terminal pentapeptide (507SDRFV511) of vicilin-like seed storage protein 22 (VL22). Structural comparison with the apo form of VSR1 reveals conformational changes in four switch regions in the PA domain. VL22 binds to a cradle of VSR1 formed by residues in the cargo-binding loop, the switch I and III regions. The C-terminal carboxyl group of VL22 is recognized by forming salt bridges with the invariant Arg95 of VSR1. Compared with the structure of VSR1-PA in complex with the ctVSD of cruciferin 1, VL22 makes extra hydrophobic interactions with the cargo-binding loop and hydrogen bonds with switch I residues in VSR1. Tagging the C-terminal sequence of VL22, but not VL22-R509P, VL22-V511P, VL22-R509P-V511P nor vicilin-like seed storage protein 43 (VL43), redirected secretory red fluorescent protein (spRFP) to the vacuoles in Arabidopsis protoplasts. Scanning mutagenesis identified an E519S substitution converting the C-terminal sequence of VL43 to a sorting determinant that can redirect spRFP to the vacuoles, suggesting that charge-charge repulsion prevents the receptor-cargo interactions between VL43 and VSR1. The recognition of ctVSD by VSRs is likely promiscuous, resulting from the additive effect of individual preference of residues in the ctVSD.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144984557","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

Deciphering the molecular targets of Plasmodium and Anopheline interactions for malaria control. 破译疟原虫和按蚊相互作用的分子靶点以控制疟疾。

IF 4.2

The FEBS journal Pub Date : 2025-09-02 DOI: 10.1111/febs.70250

Sangeeta Janjoter, Divya Kataria, Nisha Dahiya, Mahima Yadav, Hitesh Singh, Shilpi Garg, Neelam Sehrawat

{"title":"Deciphering the molecular targets of Plasmodium and Anopheline interactions for malaria control.","authors":"Sangeeta Janjoter, Divya Kataria, Nisha Dahiya, Mahima Yadav, Hitesh Singh, Shilpi Garg, Neelam Sehrawat","doi":"10.1111/febs.70250","DOIUrl":"https://doi.org/10.1111/febs.70250","url":null,"abstract":"Malaria is a severe disease that is transmitted by female Anopheles mosquitoes and caused by the Plasmodium parasite. Despite a decrease in mortality rate, it continues to pose significant challenges such as resistance to antimalarial drugs and insecticides, which necessitates the need for novel malaria control and elimination strategies. To identify new molecular targets for malaria control, there is a need to understand the molecular interaction between mosquitoes and parasites. Plasmodium ookinetes interact with the mosquito midgut proteins during midgut invasion and sporozoites interact with the mosquito salivary gland (SG) proteins. These interactions are crucial for the parasite's invasion of the mosquito midgut and SG, respectively. This review explores the involvement of various Plasmodium genes in male and female gametogenesis and parasite transmission, their interaction with the mosquito genes that facilitate parasite invasion, and how the mosquito immune system defends itself from the invading parasite. Understanding the biology underlying the interaction between mosquitoes and parasites may lead to a better comprehension of the disease and could help design efficient vector control strategies.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144984501","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

Cas9 beyond CRISPR - SUMOylation, effector-like potential and pathogenic adaptation. Cas9超越CRISPR - SUMOylation，效应样潜力和致病性适应。

IF 4.2

The FEBS journal Pub Date : 2025-09-02 DOI: 10.1111/febs.70256

Umut Sahin

{"title":"Cas9 beyond CRISPR - SUMOylation, effector-like potential and pathogenic adaptation.","authors":"Umut Sahin","doi":"10.1111/febs.70256","DOIUrl":"https://doi.org/10.1111/febs.70256","url":null,"abstract":"The CRISPR/Cas9 system has revolutionized molecular biology and gene editing, yet key aspects of its regulation, especially within eukaryotic environments, remain enigmatic. In this Viewpoint article, I will speculate on and explore the provocative hypothesis that Cas9 may possess previously unrecognized effector-like functions when expressed in host cells, potentially shaped by host-mediated post-translational modifications (PTMs). Of particular interest is SUMOylation at lysine 848, a key residue for DNA binding within the catalytic site, raising the possibility that this modification is not incidental, but functionally significant and precisely regulated. SUMOylation, a eukaryotic PTM, is increasingly recognized as a mechanism that also targets bacterial and viral effector proteins and virulence factors during infection, exerting context-dependent effects that may either enhance or hinder pathogen replication. Could Cas9, beyond its canonical role in bacterial CRISPR immunity, act as a host-modulating effector during infection, akin to known bacterial nucleomodulins such as transcription activator-like (TAL) effectors? If so, this would imply that certain pathogenic bacteria may have evolved Cas9 variants capable of exploiting host PTM machinery and targeting the host genome-an adaptation with potential implications for microbial virulence, host-pathogen interactions, and co-evolutionary dynamics. This perspective underscores the importance of systematically mapping Cas9 PTMs and examining their evolutionary conservation, functional significance, and pharmacological tunability, not only for basic biological insight and to deepen our understanding of microbial strategies, but also to refine the precision and safety of Cas9-based therapeutic platforms.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144984518","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

TDP-43 proteinopathies and neurodegeneration: insights from Caenorhabditis elegans models. TDP-43蛋白病变和神经退行性变：秀丽隐杆线虫模型的见解。

IF 4.2

The FEBS journal Pub Date : 2025-09-02 DOI: 10.1111/febs.70239

Ghulam Jeelani Pir, Joerg Buddenkotte, Majid Ali Alam, Ahmed Own, Randall J Eck, Brian C Kraemer, Eckhard Mandelkow, Martin Steinhoff

{"title":"TDP-43 proteinopathies and neurodegeneration: insights from Caenorhabditis elegans models.","authors":"Ghulam Jeelani Pir, Joerg Buddenkotte, Majid Ali Alam, Ahmed Own, Randall J Eck, Brian C Kraemer, Eckhard Mandelkow, Martin Steinhoff","doi":"10.1111/febs.70239","DOIUrl":"https://doi.org/10.1111/febs.70239","url":null,"abstract":"TDP-linked proteinopathies, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE), are characterised by pathogenic deposits containing transactive response DNA-binding protein 43 (TDP-43) in the brain and spinal cord of patients. These hallmark pathological features are associated with widespread neuronal dysfunction and progressive neurodegeneration. TDP-43's role as an essential RNA/DNA-binding protein in RNA metabolism and gene expression regulation is clear, but deciphering the intricate pathophysiological mechanisms underpinning TDP-43-mediated neurodegeneration is paramount for developing effective therapies and novel diagnostic tools for early detection before frank neuronal loss occurs. The nematode Caenorhabditis elegans, with highly conserved TDP-43 orthologue TDP-1, serves as a powerful genetic model to investigate the molecular underpinnings of TDP-43 proteinopathies. Here, we provide a brief overview of the structural and functional characteristics of TDP-43 and TDP-1, highlighting their conserved roles in RNA metabolism, stress responses, and neurodegeneration. We then delve into the pathobiology of TDP-43, drawing insights from C. elegans models expressing either monogenic TDP-43 variants or bigenic combinations with ALS-associated risk genes, and discuss how these models have advanced our understanding of the pathomechanisms of TDP-43 proteinopathies. By employing its simplicity and genetic manipulability, we discuss how these models have helped identify chemical and genetic suppressors of TDP-43-induced phenotypes, including small molecules like Pimozide and the probiotic Lacticaseibacillus rhamnosus HA-114, now in clinical trials. This review underscores the translational value of C. elegans in unraveling the biochemical pathways and interactions in TDP-43 proteinopathies that perturb cellular physiology, potentially facilitating mechanism-based therapy development.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144984524","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

Autophagy and exosomes play different roles in the disposal of unwanted cellular materials. 自噬和外泌体在处理不需要的细胞物质中起着不同的作用。

IF 4.2

The FEBS journal Pub Date : 2025-09-02 DOI: 10.1111/febs.70244

Kedan Mao, Lin Wei, Fangfang Huo, Sidong Xiong, Yuxuan Fu

{"title":"Autophagy and exosomes play different roles in the disposal of unwanted cellular materials.","authors":"Kedan Mao, Lin Wei, Fangfang Huo, Sidong Xiong, Yuxuan Fu","doi":"10.1111/febs.70244","DOIUrl":"https://doi.org/10.1111/febs.70244","url":null,"abstract":"Degradative autophagy supplies a source of nutrients and energy by digesting cytoplasmic components. Additionally, it eliminates toxic protein aggregates and defective organelles from cells. Exosomes are small vesicles that are released by cells into the extracellular environment and are also involved in maintenance of homeostasis by removing unwanted materials and intracellular pathogens. Nevertheless, it remains unclear how these two processes may differ or are alike in their roles in maintaining intracellular homeostasis. In this study, we found that secretory exosomes served as a quality control mechanism, maintaining intracellular RNA homeostasis by facilitating both the selective packaging of endogenous and exogenous RNA species. Conversely, autophagic degradation primarily functions to dispose of both endogenous and exogenous proteins, resulting in controlling intracellular proteostasis. The depletion of exosome secretion resulted in prolonged accumulation of exogenous RNA within the cells, whereas it had no significant effect on the accumulation of exogenous proteins. Viral infection not only induced the host autophagy response, but also impacted secretion of exosomes. Our data showed that secretory exosomes contributed to the clearing of increased intracellular microRNAs induced by enterovirus infection, thereby weakening viral replication. Furthermore, the secretory exosomes were essential for the disposal of viral RNA replicon rather than autophagic degradation, thereby facilitating host survival. Our results collectively revealed that both secretory exosome and autophagic degradation were crucial for maintaining cellular homeostasis, but that they operate through distinct mechanisms and dispose of different types of unwanted materials.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144984460","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

Propionibacterium acnes evades microbicidal phagocytosis by inhibiting the mitochondrial biogenesis of nucleus pulposus cells. 痤疮丙酸杆菌通过抑制髓核细胞的线粒体生物发生来逃避杀微生物吞噬作用。

IF 4.2

The FEBS journal Pub Date : 2025-09-02 DOI: 10.1111/febs.70247

Lemeng Ren, Changwei Li, Juntao Sun, Yuehuan Zheng, Yucheng Jiao, Jiancheng Zheng, Fangke Zhang, Yazhou Lin, Wenjian Wu, Peng Cao

{"title":"Propionibacterium acnes evades microbicidal phagocytosis by inhibiting the mitochondrial biogenesis of nucleus pulposus cells.","authors":"Lemeng Ren, Changwei Li, Juntao Sun, Yuehuan Zheng, Yucheng Jiao, Jiancheng Zheng, Fangke Zhang, Yazhou Lin, Wenjian Wu, Peng Cao","doi":"10.1111/febs.70247","DOIUrl":"https://doi.org/10.1111/febs.70247","url":null,"abstract":"Although an increasing number of investigators confirm the latent infection of Propionibacterium acnes in degenerated nucleus pulposus tissue, the molecular mechanism by which P. acnes evades being eliminated and establishes persistent colonization in the nucleus pulposus (NP) tissue remains unknown. In this study, we ascertained that despite the resistance by nucleus pulposus cells (NPCs) to the invasion of P. acnes through microbicidal phagocytosis, P. acnes is able to nevertheless promote its long-term colonization by inhibiting the sustained bactericidal capability of NPCs. This allows P. acnes to reside in intervertebral discs for an extended period, ultimately inducing chronic infectious intervertebral disc degeneration (IVDD). Mechanistically, P. acnes impairs the mitochondrial biogenesis of NPCs through the AMPK/SIRT-1/PGC-1α signaling pathway. This results in impaired mitochondria that are unable to generate sufficient ATP and deliver mitochondrial reactive oxygen species (mROS) to carry out the bactericidal process effectively, thus hampering the sustained microbicidal function. These findings provide novel insights into how P. acnes evades being phagocytosed and killed by NPCs and may offer potential therapeutic targets for the treatment of infectious IVDD.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144984529","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

Biostimulants in plant brassinosteroid hormone receptor BRI1 activation-a new system to evaluate activation capacity. 植物油菜素内酯激素受体BRI1激活中的生物刺激物——一种评估激活能力的新系统。

IF 4.2

The FEBS journal Pub Date : 2025-08-28 DOI: 10.1111/febs.70235

Maribel Marquina, Montserrat Ricart-Fort, Rocío Díaz-Parra, Sandra López-Avilés, Tula Yance, Pablo Quirós, Elena Contreras, Ignasi Salaet, Sergio Atares, Rosa Aligué

{"title":"Biostimulants in plant brassinosteroid hormone receptor BRI1 activation-a new system to evaluate activation capacity.","authors":"Maribel Marquina, Montserrat Ricart-Fort, Rocío Díaz-Parra, Sandra López-Avilés, Tula Yance, Pablo Quirós, Elena Contreras, Ignasi Salaet, Sergio Atares, Rosa Aligué","doi":"10.1111/febs.70235","DOIUrl":"https://doi.org/10.1111/febs.70235","url":null,"abstract":"The search for innovative and alternative chemical methods to manage plant growth is an ever-increasing reality. Biostimulants, products of biological origin, have shown promise in improving various agronomic characteristics and boosting yield. However, the selection and characterization of biostimulant matrices is a complex process that requires rigorous evaluation adapted to the specific needs of each plant. Because mixtures of biologically active compounds are present in biostimulants, efficient methods are required to characterize their potential mode of action. In this study, a new approach was developed to assess the biological activity of biostimulants by activating specific plant receptors involved in key physiological processes. It is based on the heterologous expression in fission yeast of brassinosteroid receptor protein Brassinosteroid Insensitive 1 (BRI1), which is involved in plant growth and development, and its specific activation by brassinolide (BL). The method involves the identification of highly expressed genes in response to BL activation of the BRI1 receptor, to generate a GFP reporter gene system that is switched on when biostimulants activate the BRI1 receptor. The biostimulants selected for testing were hydrolysates of animal origin. The results not only revealed variations in BRI1 activation among biostimulants, but also highlighted that samples from the same origin exhibit different BRI1 activation capacities depending on their processing methods. This new method enables direct classification of the mode of action of biostimulants by assessing their ability to activate specific plant receptors, providing a valuable resource for biostimulant research and development.","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":"144984462","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