The FEBS journal最新文献_第4页

Modifying inhibitor specificity for homologous enzymes by machine learning. 通过机器学习修饰抑制剂对同源酶的特异性。

IF 4.2

The FEBS journal Pub Date : 2025-09-05 DOI: 10.1111/febs.70249

Dor S Gozlan, Reut Meiri, Gili Shapira, Matt Coban, Evette S Radisky, Yaron Orenstein, Niv Papo

{"title":"Modifying inhibitor specificity for homologous enzymes by machine learning.","authors":"Dor S Gozlan, Reut Meiri, Gili Shapira, Matt Coban, Evette S Radisky, Yaron Orenstein, Niv Papo","doi":"10.1111/febs.70249","DOIUrl":"https://doi.org/10.1111/febs.70249","url":null,"abstract":"Selective inhibitors are essential for targeted therapeutics and for probing enzyme functions in various biological systems. The two main challenges in identifying such protein-based inhibitors lie in the extensive experimental effort required, including the generation of large libraries, and in tailoring the selectivity of inhibitors to enzymes with homologous structures. To address these challenges, machine learning (ML) is being used to improve protein design by training on targeted libraries and identifying key interface mutations that enhance affinity and specificity. However, such ML-based methods are limited by inaccurate energy calculations and difficulties in predicting the structural impacts of multiple mutations. Here, we present an ML-based method that leverages HTS data to streamline the design of selective protease inhibitors. To demonstrate its utility, we applied our new method to find inhibitors of matrix metalloproteinases (MMPs), a family of homologous proteases involved in both physiological and pathological processes. By training ML models on binding data for three MMPs (MMP-1, MMP-3, and MMP-9), we successfully designed a novel N-TIMP2 variant with a differential specificity profile, namely, high affinity for MMP-9, moderate affinity for MMP-3, and low affinity for MMP-1. Our experimental validation showed that this novel variant exhibited a significant specificity shift and enhanced selectivity compared with wild-type N-TIMP2. Through molecular modeling and energy minimization, we obtained structural insights into the variant's enhanced selectivity. Our findings highlight the power of ML-based methods to reduce experimental workloads, facilitate the rational design of selective inhibitors, and advance the understanding of specific inhibitor-enzyme interactions in homologous enzyme systems.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006984","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

PU.1 and TGF-β signaling activate the cell-surface expression of CD103 in mast cells and dendritic cells: opposite roles of GATA2 in the expression of mucosal mast cell genes. PU.1和TGF-β信号激活肥大细胞和树突状细胞中CD103的细胞表面表达：GATA2在粘膜肥大细胞基因表达中的作用相反。

IF 4.2

The FEBS journal Pub Date : 2025-09-04 DOI: 10.1111/febs.70252

Kenta Ishii, Kazuki Nagata, Niya Yamashita, Yuki Yamazaki, Yuta Akimoto, Weiting Zhao, Mariko Inoue, Naoto Ito, Kazumi Kasakura, Chiharu Nishiyama

{"title":"PU.1 and TGF-β signaling activate the cell-surface expression of CD103 in mast cells and dendritic cells: opposite roles of GATA2 in the expression of mucosal mast cell genes.","authors":"Kenta Ishii, Kazuki Nagata, Niya Yamashita, Yuki Yamazaki, Yuta Akimoto, Weiting Zhao, Mariko Inoue, Naoto Ito, Kazumi Kasakura, Chiharu Nishiyama","doi":"10.1111/febs.70252","DOIUrl":"https://doi.org/10.1111/febs.70252","url":null,"abstract":"Mucosal mast cells (MMCs) are distinguished from connective tissue mast cells (MCs) by the specific cell-surface expression of integrin CD103 (also known as integrin αE/β7; αE is encoded by Itgae) and mast cell protease 1 and 2 (Mcpt1 and Mcpt2, respectively). Although the expression of the Mcpt1 and Mcpt2 genes is cooperatively regulated by the transcription factor GATA-binding protein 2 (GATA2) and transforming growth factor beta (TGF-β) signaling in MMCs, the transcriptional mechanism of the cell-surface expression of CD103 remains unknown. We herein found that surface CD103 and Itgae mRNA levels were significantly increased by the knockdown (KD) of Gata2 in mouse bone marrow-derived MCs (BMMCs), which was accelerated by TGF-β stimulation. Since the mRNA levels of Spi1 (encoding transcription factor PU.1) were increased in Gata2 KD BMMCs, we examined the effects of PU.1 on the cell-surface expression of CD103. As expected, CD103 levels on BMMCs were significantly decreased by Spi1 KD and increased by Spi1 overexpression. Spi1 KD suppressed Itgae expression even in the presence of TGF-β in BMMCs and peritoneal MCs, whereas Gata2 KD amplified the TGF-β-induced increase in Itgae expression. The amount of PU.1 binding to the cis-element in the Itgae gene was significantly and moderately increased by Gata2 KD and TGF-β stimulation, respectively. Since PU.1 is an essential transcription factor for dendritic cells (DCs), we examined the role of PU.1 in CD103 cell-surface expression on DCs. The KD experiment using bone marrow-derived DCs (BMDCs) showed a significant decrease in CD103 levels in Spi1-siRNA-transfected BMDCs. We concluded that PU.1 affected CD103 expression on MMCs and DCs by transactivating the Itgae gene, and also that GATA2, which positively regulated the MMC-specific expression of Mcpt1 and Mcpt2, inhibited the cell-surface expression of CD103 by repressing PU.1.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995066","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

The genomic SELEX-based method identifies 350 SigA-specific promoters in Mycobacterium tuberculosis. 基于基因组selex的方法鉴定了结核分枝杆菌中350个siga特异性启动子。

IF 4.2

The FEBS journal Pub Date : 2025-09-03 DOI: 10.1111/febs.70251

Ritu Jaiswal, Subhajit Dutta, Soumya Mukherjee, Nilanjana Hazra, Sudipto Saha, Jayanta Mukhopadhyay

{"title":"The genomic SELEX-based method identifies 350 SigA-specific promoters in Mycobacterium tuberculosis.","authors":"Ritu Jaiswal, Subhajit Dutta, Soumya Mukherjee, Nilanjana Hazra, Sudipto Saha, Jayanta Mukhopadhyay","doi":"10.1111/febs.70251","DOIUrl":"https://doi.org/10.1111/febs.70251","url":null,"abstract":"The gene regulation in Mycobacterium tuberculosis by different sigma factors, including the principal sigma factor, sigmaA (SigA), is poorly understood. Here, we have developed a modified genomic systematic evolution of ligands by exponential enrichment (SELEX)-Seq approach that identifies 350 new SigA-binding sites in M. tuberculosis. SigA-binding ability and promoter activity of representative DNA sequences were confirmed by electrophoretic mobility shift assay (EMSA) and reporter assay, respectively. Among these DNA sequences, 38 are located in the intergenic region, indicating these regions as possible SigA promoters of the surrounding genes. The remaining 312 DNA sequences are located within the intragenic region, suggesting a previously unknown role of these binding sites, including SigA-dependent regulatory roles. We reveal that the intragenic SigA-binding sites are responsible for synthesizing 62 transcripts and 14 noncoding RNAs from the existing database. We have further identified 88 new proteins, different from annotated open reading frames (ORFs) in the genome sequences, downstream of the intragenic SigA-binding sites. Out of 350 SigA-binding sites, (a) 156 sequences contain -10 elements (T[C][N][N]N[T]) with a certain degree of degeneracy, including 38 having an additional extended -10 TG sequence, (b) 66 DNA sequences contain both -35 (T[G/T][G/T][C/T][N][C]) and -10 elements with a spacer of 5-25 bp, and (c) intriguingly, 128 SigA-binding sites contain only 35-like elements. Thus, our study reveals that the promoter architecture of M. tuberculosis significantly differs from the generalized concept of bacterial promoters and opens a new avenue to study gene regulation in M. tuberculosis.","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":"144994519","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 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

Synthetic trap-peptides identify a TOM complex phosphatase - PP2A dephosphorylates Tom6. 合成陷阱肽鉴定TOM复合磷酸酶- PP2A去磷酸化Tom6。

IF 4.2

The FEBS journal Pub Date : 2025-09-02 DOI: 10.1111/febs.70246

Laura Scheinost, Christina Ludwig, Nico Höfflin, Asli Aras Taskin, Adinarayana Marada, F-Nora Vögtle, Chris Meisinger, Maja Köhn

{"title":"Synthetic trap-peptides identify a TOM complex phosphatase - PP2A dephosphorylates Tom6.","authors":"Laura Scheinost, Christina Ludwig, Nico Höfflin, Asli Aras Taskin, Adinarayana Marada, F-Nora Vögtle, Chris Meisinger, Maja Köhn","doi":"10.1111/febs.70246","DOIUrl":"https://doi.org/10.1111/febs.70246","url":null,"abstract":"The identification of phosphatases that dephosphorylate specific sites in proteins remains a major challenge, particularly for the major class of serine/threonine-specific phosphatases, which function as holoenzymes. Here, we report the development of synthetic trap-peptides to identify phosphatases that bind to Tom6, a subunit of the mitochondrial translocase of the outer membrane (TOM) complex. The TOM complex is regulated by reversible phosphorylation, and although responsible kinases have been identified, the corresponding phosphatases so far remain unknown. Here, the trap-peptides enriched phosphoserine/threonine-specific protein phosphatases 2A (PP2A) and 4 (PP4) as full holoenzymes from yeast cytosolic fractions. We observed that their interaction with Tom6 was mediated through their regulatory subunits Cdc55reg and Psy2reg, respectively, and that PP2A was able to dephosphorylate Ser16 of Tom6 in vitro. In summary, synthetic trap-peptides facilitate the identification of complete holoenzymes that bind to the target sequence and reveal PP2A as the first TOM phosphatase.","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":"144984549","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