The FEBS journal最新文献_第9页

Redox imbalance and hypoxia-inducible factors: a multifaceted crosstalk.

The FEBS journal Pub Date : 2025-02-11 DOI: 10.1111/febs.70013

Ravi, Jogender Singh

{"title":"Redox imbalance and hypoxia-inducible factors: a multifaceted crosstalk.","authors":"Ravi, Jogender Singh","doi":"10.1111/febs.70013","DOIUrl":"https://doi.org/10.1111/febs.70013","url":null,"abstract":"Redox homeostasis, the delicate balance between oxidative and reductive processes, is crucial for cellular function and overall organismal health. At the molecular level, cells need to maintain a fine balance between the levels of reactive oxygen species (ROS) and reducing equivalents such as glutathione and nicotinamide adenine dinucleotide phosphate. The perturbation of redox homeostasis due to excessive ROS production leads to oxidative stress that can damage lipids, proteins, and nucleic acids. Conversely, an overly reduced cellular environment due to overabundant reducing equivalents results in reductive stress, which also interferes with important cellular signaling and physiological processes. Disrupted redox homeostasis is linked to various pathological conditions, including neurodegenerative diseases, inflammatory diseases, cancer, and cardiovascular diseases. Cells employ diverse mechanisms to manage redox imbalance. The hypoxia response pathway, mediated by hypoxia-inducible factors and responsible for sensing and defending against low oxygen levels, plays a vital role in maintaining redox homeostasis. In this review, we highlight the complex and multifaceted crosstalk between hypoxia-inducible factors and redox homeostasis and discuss avenues for future research. Understanding the molecular mechanisms that link hypoxia-inducible factors to oxidative and reductive stresses is essential for comprehending several pathological conditions associated with hypoxia and redox imbalance.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143392813","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

Past, present, and future strategies for detecting and quantifying circular RNA variants.

The FEBS journal Pub Date : 2025-02-11 DOI: 10.1111/febs.70012

He Lin, Vanessa M Conn, Simon J Conn

{"title":"Past, present, and future strategies for detecting and quantifying circular RNA variants.","authors":"He Lin, Vanessa M Conn, Simon J Conn","doi":"10.1111/febs.70012","DOIUrl":"https://doi.org/10.1111/febs.70012","url":null,"abstract":"Circular RNAs (circRNAs) are a family of covalently closed RNA transcripts ubiquitous across the eukaryotic kingdom. CircRNAs are generated by a class of alternative splicing called backsplicing, with the resultant circularization of a part of parental RNA producing the characteristic backsplice junction (BSJ). Because of the noncontiguous sequence of the BSJ with respect to the DNA genome, circRNAs remained hidden in plain sight through over a decade of RNA next-generation sequencing, yet over 3 million unique circRNA transcripts have been illuminated in the past decade alone. CircRNAs are expressed in a cell type-specific manner, are highly stable, with many examples of circRNAs being evolutionarily conserved and/or functional in specific contexts. However, circRNAs can be very lowly expressed and predictions of the circRNA context from BSJ-spanning reads alone can confound extrapolation of the exact sequence composition of the circRNA transcript. For these reasons, specific and ultrasensitive detection, combined with enrichment, bespoke bioinformatics pipelines and, more recently, long-read, highly processive sequencing is becoming critical for complete characterization of all circRNA variants. Concomitantly, the need for targeted detection and quantification of specific circRNAs has sparked numerous laboratory-based and commercial approaches to visualize circRNAs in cells and quantify them in biological samples, including biospecimens. This review focuses on advancements in the detection and quantification of circRNAs, with a particular focus on recent next-generation sequencing approaches to bolster detection of circRNA variants and accurately normalize between sequencing libraries.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401073","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

Intercellular mitochondrial transfer contributes to microenvironmental redirection of cancer cell fate.

The FEBS journal Pub Date : 2025-02-11 DOI: 10.1111/febs.70002

Julie Sofie Bjerring, Yara Khodour, Emilee Anne Peterson, Patrick Christian Sachs, Robert David Bruno

{"title":"Intercellular mitochondrial transfer contributes to microenvironmental redirection of cancer cell fate.","authors":"Julie Sofie Bjerring, Yara Khodour, Emilee Anne Peterson, Patrick Christian Sachs, Robert David Bruno","doi":"10.1111/febs.70002","DOIUrl":"https://doi.org/10.1111/febs.70002","url":null,"abstract":"The mammary microenvironment has been shown to suppress tumor progression by redirecting cancer cells to adopt a normal mammary epithelial progenitor fate in vivo. However, the mechanism(s) by which this alteration occurs has yet to be defined. Here, we test the hypothesis that mitochondrial transfer from normal mammary epithelial cells to breast cancer cells plays a role in this redirection process. We evaluate mitochondrial transfer in 2D and 3D organoids using our unique 3D bioprinting system to produce chimeric organoids containing normal and cancer cells. We demonstrate that breast cancer tumoroid growth is hindered following interaction with mammary epithelial cells in both 2D and 3D environments. Furthermore, we show mitochondrial transfer occurs between donor mammary epithelial cells and recipient cancer cells primarily through tunneling nanotubes (TNTs) with minimal amounts seen from extracellular transfer of mitochondria, likely via extracellular vesicles (EVs). This organelle exchange results in various cellular and metabolic alterations within cancer cells, reducing their proliferative potential, and making them susceptible to microenvironmental control. Our results demonstrate that mitochondrial transfer contributes to microenvironmental redirection of cancer cells through alteration of metabolic and molecular functions of the recipient cancer cells. To the best of our knowledge, this is the first description of a 3D bioprinter-assisted organoid system for studying mitochondrial transfer. These studies are also the first mechanistic insights into the process of mammary microenvironmental redirection of cancer and provide a framework for new therapeutic strategies to control cancer.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401132","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

FXR suppress Müller cell activation by regulating cGAS/STING pathway in diabetic retinopathy.

The FEBS journal Pub Date : 2025-02-11 DOI: 10.1111/febs.17421

Zi-Li Wang, Xin-Yu Zhang, Cheng-Ye Tan, Miao Zhuang, Lingpeng Zhu, Xin-Hua Zheng, Yong Yao, Ting-Ting Wei

{"title":"FXR suppress Müller cell activation by regulating cGAS/STING pathway in diabetic retinopathy.","authors":"Zi-Li Wang, Xin-Yu Zhang, Cheng-Ye Tan, Miao Zhuang, Lingpeng Zhu, Xin-Hua Zheng, Yong Yao, Ting-Ting Wei","doi":"10.1111/febs.17421","DOIUrl":"https://doi.org/10.1111/febs.17421","url":null,"abstract":"Diabetic retinopathy (DR) is widely acknowledged as an ocular complication of diabetes mellitus involving retinal inflammation and secondary neuro/microvascular degeneration. Müller glial cells play a crucial role in regulating retinal homeostasis and neuroinflammation within the retina. Farnesoid X nuclear receptor (FXR) has emerged as a potential regulator of metabolic homeostasis and inflammatory responses as a bile acid nuclear receptor. However, its precise role in DR remains unclear. In order to investigate the effect of FXR on DR, we employed Sprague-Dawley rats treated with streptozotocin (STZ) and human Müller glial cells treated with advanced glycation end products (AGEs) or high glucose with palmitate (HG + PA). Our investigations revealed downregulation of FXR in DR. Furthermore, we demonstrated that activating FXR could mitigate the progression of DR, with its protective effects linked to the inhibition of inflammatory responses within Müller cells. Mechanistically, FXR could ameliorate mitochondrial dysfunction and suppress the opening of the mitochondrial permeability transition pore. This action blocked the release of mitochondrial DNA (mtDNA) from the mitochondria into the cytoplasm, thereby inhibiting the abnormal activation of the cGAS/STING pathway in DR. Further studies revealed that FXR upregulates mitochondrial transcription factor A (TFAM) by modulating ATF4/NRF1, ultimately enhancing mitochondrial function. Knockdown of FXR reversed the above effects. Additionally, FXR activation effectively rescued mitochondrial dysfunction, as evidenced by Tunicamycin (TUN)-mediated assays, further validating our findings. In summary, our findings suggest that targeting FXR may offer promising strategies for future therapeutic interventions in the treatment of DR.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143392801","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

α-Ketoglutarate inhibits the pluripotent-to-totipotent state transition in stem cells.

The FEBS journal Pub Date : 2025-02-10 DOI: 10.1111/febs.70008

Mengran Yin, Yan Li, Zhenzhu Sun, Xinyu Wu, Liang Ding, Qiang Zhang, Hai Zhou, Man Zhang, Dajiang Qin, Baoming Qin, Lulu Wang

{"title":"α-Ketoglutarate inhibits the pluripotent-to-totipotent state transition in stem cells.","authors":"Mengran Yin, Yan Li, Zhenzhu Sun, Xinyu Wu, Liang Ding, Qiang Zhang, Hai Zhou, Man Zhang, Dajiang Qin, Baoming Qin, Lulu Wang","doi":"10.1111/febs.70008","DOIUrl":"https://doi.org/10.1111/febs.70008","url":null,"abstract":"In early mouse embryogenesis, the distinct enrichment of α-ketoglutarate (αKG) in blastocysts and L-2-hydroxyglutarate (L-2HG) in 2-cell (2C) embryos serves as a key metabolic signature. While elevated L-2HG levels inhibit the resolution of totipotency during the transition from the 2C stage to the blastocyst, the role of αKG remains elusive. Mouse embryonic stem cells (mESCs) cultured in vitro naturally harbor a subpopulation that transitions dynamically into a 2C-like totipotent state, providing a convenient model to investigate the role of αKG in totipotency reprogramming. This study demonstrates that αKG significantly inhibits the pluripotency to totipotency transition through upregulating ten-eleven translocation (TET) DNA hydroxylases. We further show that reducing endogenous αKG levels via glutamine withdrawal or inhibiting αKG-dependent dioxygenases by blocking succinate dehydrogenase (SDH) markedly enhances the induction of 2C-like cells (2CLCs). Finally, leveraging the potent SDH inhibitor dimethyl malonate (DMM), we have developed a highly efficient protocol for 2CLC induction, producing cells that transcriptionally resemble mid-to-late 2C embryos. Our findings deepen the understanding of the metabolic regulation of totipotency and provide a previously undescribed approach for capturing totipotent-like stem cells in vitro.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143392825","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

Structure predictions of MuRF1-UBE2 complexes identify amino acid residues governing interaction selectivity for each MuRF1-E2 pair.

The FEBS journal Pub Date : 2025-02-10 DOI: 10.1111/febs.70017

Agnès Claustre, Mélodie Malige, Maëlys Macheton, Lydie Combaret, Etienne Lefai, Pierre Fafournoux, Daniel Taillandier, Julien Henri, Cécile Polge

{"title":"Structure predictions of MuRF1-UBE2 complexes identify amino acid residues governing interaction selectivity for each MuRF1-E2 pair.","authors":"Agnès Claustre, Mélodie Malige, Maëlys Macheton, Lydie Combaret, Etienne Lefai, Pierre Fafournoux, Daniel Taillandier, Julien Henri, Cécile Polge","doi":"10.1111/febs.70017","DOIUrl":"https://doi.org/10.1111/febs.70017","url":null,"abstract":"The RING-type E3 ubiquitin-protein ligase MuRF1 (also known as TRIM63) plays an important role in skeletal muscle atrophy by targeting contractile proteins. In cellulo, MuRF1 can alternatively interact with four E2 enzymes (UBE2E1, UBE2J1, UBE2J2, or UBE2L3), suggesting different functions or targets for the four MuRF1-E2 complexes. In this article, we studied the interface of these MuRF1-UBE2 complexes based on AlphaFold2 and AlphaFold3 predictions. These predictions revealed the involvement of different residues at the interface of each complex. We confirmed this overall interface difference by the differential sensitivity of MuRF1-E2 complexes to regenerating solutions in surface plasmon resonance experiments. We further confirmed several predictions individually by affinity measurements with point-mutant E2 enzymes and truncated MuRF1. We used the interaction-induced fluorescence change approach with fluorescent MuRF1. Besides canonical E2-RING-type E3 interactions, we were able to identify selective contact points between MuRF1 and its UBE2 partners. Furthermore, in the case of the MuRF1-E2E1 pair, unlike the other MuRF1-E2 pairs, the interaction may also be governed by a domain outside the RING domain. Since the function of RING-type E3s is regulated by E2 enzymes, deciphering the mechanisms of selective recruitment of E2s by MuRF1 paves the way for the development of targeted therapeutics to fight muscle atrophy.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143392821","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

Molecular mechanisms of hotspot variants in cytoskeletal β-actin associated with Baraitser-Winter syndrome.

The FEBS journal Pub Date : 2025-02-10 DOI: 10.1111/febs.70018

Johannes N Greve, Dietmar J Manstein

{"title":"Molecular mechanisms of hotspot variants in cytoskeletal β-actin associated with Baraitser-Winter syndrome.","authors":"Johannes N Greve, Dietmar J Manstein","doi":"10.1111/febs.70018","DOIUrl":"https://doi.org/10.1111/febs.70018","url":null,"abstract":"Baraitser-Winter cerebrofrontofacial syndrome (BWCFF) is the most common and best-defined clinical entity associated with heterozygous single-point missense mutations in cytoskeletal β-actin. Patients present with distinct craniofacial anomalies and neurodevelopmental disabilities of variable severity. To date, the most frequently observed variants affect residue R196 of cytoskeletal β-actin. Patients carrying the p.R196 variants are likely to suffer from pachygyria, probably due to neuronal migration defects contributing to the development of abnormal convolutions of the cerebral cortex. Here, we report on the recombinant production, purification and characterization of the BWCFF hotspot variants p.R196H, p.R196C and p.R196S. Our findings reveal that the stability of the monomeric variants remains unaffected, suggesting that the disease mechanism involves the incorporation of these variants into actin filaments. This incorporation alters F-actin stability and polymerization dynamics to varying degrees, depending on the specific variant. These effects are consistent with the positioning of residue R196 near the helical filament axis. Observed changes include an increased critical concentration for polymerization, reduced elongation rates and accelerated filament depolymerization. Within the actin-related protein 2/3 (Arp2/3)-generated branch junction complex, which is critical for processes such as cell migration and endocytosis, residue R196 is located at the interface between the first protomer of the nucleated filament and the Arp2 subunit. Variant p.R196H specifically results in reduced branching efficiency and impaired branch stability. Future research will seek to elucidate the impact of these actin filament defects on cellular processes and their contribution to the multifaceted pathophysiology of BWCFF, with a particular emphasis on cortical development.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143392805","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

Phosphatidic acid induces cytoskeletal rearrangements through the Src-FAK-RhoA/ROCK signaling pathway during decidualization.

The FEBS journal Pub Date : 2025-02-10 DOI: 10.1111/febs.17412

Hyeon-Jeong Jun, So Young Lee, Shin-Young Park, Joong Sub Choi, Mee-Sup Yoon, Joong-Soo Han

{"title":"Phosphatidic acid induces cytoskeletal rearrangements through the Src-FAK-RhoA/ROCK signaling pathway during decidualization.","authors":"Hyeon-Jeong Jun, So Young Lee, Shin-Young Park, Joong Sub Choi, Mee-Sup Yoon, Joong-Soo Han","doi":"10.1111/febs.17412","DOIUrl":"https://doi.org/10.1111/febs.17412","url":null,"abstract":"Decidualization, the transformation of human endometrial stromal cells from a fibroblast-like to a rounded morphology, is crucial for creating a receptive intrauterine environment that supports successful embryo implantation. While decidual markers such as insulin-like growth factor-binding protein 1 and prolactin are well studied, the specific signaling mechanisms underlying morphological changes during decidualization remain unclear. In this study, we identified the phosphatidic acid (PA)-Src-focal adhesion kinase (FAK)-RhoA/Rho-associated protein kinase (ROCK) signaling pathway as a critical regulator of cytoskeletal rearrangement during PA-induced decidualization in human endometrial stromal cells. PA, a product of phospholipase D1, activates FAK, initiating a cascade of events involving Src-family kinases and RhoA signaling, ultimately leading to the cytoskeletal changes necessary for decidualization. Our in vitro experiments showed that PA-induced decidualization involved the formation of stress fibers mediated by ROCK activation. The traditional decidual markers, insulin-like growth factor-binding protein 1 and prolactin, did not significantly influence these morphological changes, suggesting that the PA-induced pathway operates independently of these markers. In vivo studies in ovariectomized mice demonstrated that PA injection into the uterine horn increased the uterine cavity weight and wall thickness, reinforcing the role of PA in promoting decidualization. These findings highlight the importance of the PA-Src-FAK-RhoA-ROCK pathway in regulating cytoskeletal dynamics during decidualization and suggest potential therapeutic targets for addressing implantation-associated infertility.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143384405","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

Activating AMPK improves pathological phenotypes due to mtDNA depletion.

The FEBS journal Pub Date : 2025-02-07 DOI: 10.1111/febs.70006

Gustavo Carvalho, Tran V H Nguyen, Bruno Repolês, Josefin M E Forslund, W M Ruchitha Rukmal Wijethunga, Farahnaz Ranjbarian, Isabela C Mendes, Choco Michael Gorospe, Namrata Chaudhari, Micol Falabella, Mara Doimo, Sjoerd Wanrooij, Robert D S Pitceathly, Anders Hofer, Paulina H Wanrooij

{"title":"Activating AMPK improves pathological phenotypes due to mtDNA depletion.","authors":"Gustavo Carvalho, Tran V H Nguyen, Bruno Repolês, Josefin M E Forslund, W M Ruchitha Rukmal Wijethunga, Farahnaz Ranjbarian, Isabela C Mendes, Choco Michael Gorospe, Namrata Chaudhari, Micol Falabella, Mara Doimo, Sjoerd Wanrooij, Robert D S Pitceathly, Anders Hofer, Paulina H Wanrooij","doi":"10.1111/febs.70006","DOIUrl":"https://doi.org/10.1111/febs.70006","url":null,"abstract":"AMP-activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis that also plays a role in preserving mitochondrial function and integrity. Upon a disturbance in the cellular energy state that increases AMP levels, AMPK activity promotes a switch from anabolic to catabolic metabolism to restore energy homeostasis. However, the level of severity of mitochondrial dysfunction required to trigger AMPK activation is currently unclear, as is whether stimulation of AMPK using specific agonists can improve the cellular phenotype following mitochondrial dysfunction. Using a cellular model of mitochondrial disease characterized by progressive mitochondrial DNA (mtDNA) depletion and deteriorating mitochondrial metabolism, we show that mitochondria-associated AMPK becomes activated early in the course of the advancing mitochondrial dysfunction, before any quantifiable decrease in the ATP/(AMP + ADP) ratio or respiratory chain activity. Moreover, stimulation of AMPK activity using the specific small-molecule agonist A-769662 alleviated the mitochondrial phenotypes caused by the mtDNA depletion and restored normal mitochondrial membrane potential. Notably, the agonist treatment was able to partially restore mtDNA levels in cells with severe mtDNA depletion, while it had no impact on mtDNA levels of control cells. The beneficial impact of the agonist on mitochondrial membrane potential was also observed in cells from patients suffering from mtDNA depletion. These findings improve our understanding of the effects of specific small-molecule activators of AMPK on mitochondrial and cellular function and suggest a potential application for these compounds in disease states involving mtDNA depletion.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367215","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 analysis of the ribosome assembly factor Nep1, an N1-specific pseudouridine methyltransferase, reveals mechanistic insights.

The FEBS journal Pub Date : 2025-02-07 DOI: 10.1111/febs.70005

Sayan Saha, Shankar Prasad Kanaujia

{"title":"Structural analysis of the ribosome assembly factor Nep1, an N1-specific pseudouridine methyltransferase, reveals mechanistic insights.","authors":"Sayan Saha, Shankar Prasad Kanaujia","doi":"10.1111/febs.70005","DOIUrl":"https://doi.org/10.1111/febs.70005","url":null,"abstract":"Nucleolar essential protein 1 (Nep1; also known as ribosomal RNA small subunit methyltransferase Nep1) is a crucial factor in forming small ribosomal subunits in eukaryotes and archaea. Nep1 possesses an S-adenosyl-L-methionine (SAM)-dependent SpoU-TrmD (SPOUT) ribosomal RNA (rRNA) methyltransferase (MTase) fold and catalyzes pseudouridine (Ψ) methylation at specific sites of the small subunit (SSU) rRNA. Mutations in Nep1 proteins result in a severe developmental disorder in humans and reduced growth in yeast, suggesting its role in ribosome biogenesis. In this study, the crystal structures of Nep1 from the archaebacterium Pyrococcus horikoshii (PhNep1), both in its apo and holo (adenosine or 5-methylthioadenosine bound) forms have been reported. The structural analysis of PhNep1 revealed an α/β fold featuring a deep trefoil knot akin to the SPOUT domain, with two novel extensions-a globular loop and a β-α-β extension. Moreover, the cofactor-binding site of PhNep1 exhibits a preformed pocket, topologically similar to that of other SPOUT-class MTases. Further, structural analysis of PhNep1 revealed that it forms a homodimer coordinated by inter-subunit hydrogen bonds and hydrophobic interactions. Moreover, the results of this study indicate that PhNep1 can specifically methylate consensus RNAs, having a pseudouridine (ψ) located at position 926 of helix 35 (h35) of 16S rRNA in P. horikoshii. The stability of the Nep1-RNA complex seems to be primarily assisted by the conserved arginine residues located at the dimeric interface.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367217","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