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Effect of microglial Pd1 on glial scar formation after spinal cord injury in mice. 小胶质细胞 Pd1 对小鼠脊髓损伤后胶质瘢痕形成的影响
IF 4.8 2区 生物学
Journal of Biological Chemistry Pub Date : 2025-04-08 DOI: 10.1016/j.jbc.2025.108489
Yunyun Cai,Zhihao Lin,Xin Shen,Ming Li,Lingyan Xing,Tuo Yang,Gang Chen
{"title":"Effect of microglial Pd1 on glial scar formation after spinal cord injury in mice.","authors":"Yunyun Cai,Zhihao Lin,Xin Shen,Ming Li,Lingyan Xing,Tuo Yang,Gang Chen","doi":"10.1016/j.jbc.2025.108489","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.108489","url":null,"abstract":"The crosstalk between microglia and astrocytes following spinal cord injury (SCI) greatly decides the prognosis. However, a comprehensive understanding of the molecular mechanisms by which microglia regulate astrocytic activity post-SCI is lacking. Programmed cell death protein 1 (Pdcd1, Pd1) plays a crucial role in modulating immune responses by exerting suppressive effects on microglia and peripheral immune cells within the central nervous system (CNS). Previous studies have shown the involvement of Pd1 in the pathogenesis of SCI; however, the role of microglial Pd1 in astrocytic activation and the following glial scar formation remains elusive. Here, we demonstrated that the pharmacological depletion of microglia using minocycline decreased the expression of TNF-α and IL-6 while concurrently increasing the expression of IL-10 following SCI, thereby facilitating motor function recovery in mice. We observed an increase in Pd1 expression in the injured spinal cord after SCI, with precise localization of Pd1 within microglia. Based on Pd1 knockout (KO) mice, we further revealed that Pd1 deficiency disrupted glial scar formation, leading to increased inflammation, impeded nerve regeneration, enlarged tissue damage, and compromised functional recovery following SCI. In vitro study showed that siRNA-mediated inhibition of Pd1 in microglia followed by lipopolysaccharide (LPS) treatment significantly inhibited astrocyte migration and upregulated the secretion of TNF-α and CXCL9 from microglia, indicating that microglial Pd1 regulates glial scar formation through modulating the inflammatory microenvironment. Our study gains a new mechanistic insight into how microglial Pd1 decides the fate of SCI and promotes microglial Pd1 as a promising therapeutic target for SCI.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"65 1","pages":"108489"},"PeriodicalIF":4.8,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
HRI protein kinase in cytoplasmic heme sensing and mitochondrial stress response: relevance to hematological and mitochondrial diseases. 细胞质血红素感应和线粒体应激反应中的 HRI 蛋白激酶:与血液病和线粒体疾病的相关性。
IF 4.8 2区 生物学
Journal of Biological Chemistry Pub Date : 2025-04-08 DOI: 10.1016/j.jbc.2025.108494
Jane-Jane Chen
{"title":"HRI protein kinase in cytoplasmic heme sensing and mitochondrial stress response: relevance to hematological and mitochondrial diseases.","authors":"Jane-Jane Chen","doi":"10.1016/j.jbc.2025.108494","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.108494","url":null,"abstract":"Most iron in humans is bound in heme used as a prosthetic group for hemoglobin. Heme-regulated inhibitor (HRI) is responsible for coordinating heme availability and protein synthesis. Originally characterized in rabbit reticulocyte lysates, HRI was shown in 1976 to phosphorylate the α-subunit of eIF2, revealing a new molecular mechanism for regulating protein synthesis. Since then, HRI research has mostly been focused on the biochemistry of heme inhibition through direct binding, and heme sensing in balancing heme and globin synthesis to prevent proteotoxicity in erythroid cells. Beyond inhibiting translation of highly translated mRNAs, eIF2α phosphorylation also selectively increases translation of certain poorly translated mRNAs, notably ATF4 mRNA, for reprogramming of gene expression to mitigate stress, known as the integrated stress response (ISR). In recent years, there have been novel mechanistic insights of HRI-ISR in oxidative stress, mitochondrial function and erythroid differentiation during heme deficiency. Furthermore, HRI-ISR is activated upon mitochondrial stress in several cell types, establishing the bifunctional nature of HRI protein. The role of HRI and ISR in cancer development and vulnerability is also emerging. Excitingly, the UBR4 ubiquitin ligase complex has been demonstrated to silence the HRI-ISR by degradation of activated HRI proteins, suggesting additional regulatory processes. Together, these recent advancements indicate that the HRI-ISR mechanistic axis is a target for new therapies for hematological and mitochondrial diseases, as well as oncology. This review covers the historical overview of HRI biology, the biochemical mechanisms of regulating HRI, and the biological impacts of the HRI-ISR pathway in human diseases.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"90 1","pages":"108494"},"PeriodicalIF":4.8,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Patient-derived organotypic tissue cultures as a platform to evaluate metabolic reprogramming in breast cancer patients. 将源自患者的器官组织培养物作为评估乳腺癌患者代谢重编程的平台。
IF 4.8 2区 生物学
Journal of Biological Chemistry Pub Date : 2025-04-08 DOI: 10.1016/j.jbc.2025.108495
Teresa W -M Fan,Jing Yan,Carlos Frederico L Goncalves,Jahid M M Islam,Penghui Lin,Mohamed M Y Kaddah,Richard M Higashi,Andrew N Lane,Xiaoqin Wang,Caigang Zhu
{"title":"Patient-derived organotypic tissue cultures as a platform to evaluate metabolic reprogramming in breast cancer patients.","authors":"Teresa W -M Fan,Jing Yan,Carlos Frederico L Goncalves,Jahid M M Islam,Penghui Lin,Mohamed M Y Kaddah,Richard M Higashi,Andrew N Lane,Xiaoqin Wang,Caigang Zhu","doi":"10.1016/j.jbc.2025.108495","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.108495","url":null,"abstract":"Patient-derived organotypic tissue cultures (PD-OTC) are unique models for probing cancer metabolism and therapeutic responses. They retain patient tissue architectures/ microenvironments that are difficult to recapitulate while affording comparison of cancer (CA) versus matched non-cancer (NC) tissue responses to treatments. We have developed a long-term culturing method for fresh and cryopreserved PD-OTC of breast cancer patients bearing invasive ductal carcinoma. Five PD-OTC came from patients with treatment-naïve primary ER+/PR+/HER2- tumors while one came from a patient with neoadjuvant therapy for locally metastatic ERlow/PR-/HER2- tumor. They all exhibited tissue outgrowth in one month with some CA OTC harboring isolatable organoids and fibroblasts. We interrogated reprogrammed metabolism in CA versus paired NC OTC with dual 2H7-glucose/13C5,15N2-Gln tracers coupled with Stable Isotope-Resolved Metabolomic analysis. We noted variable activation of glycolysis, cataplerotic/anaplerotic Krebs cycle including reductive carboxylation, the pentose phosphate pathway, riboneogenesis, gluconeogenesis (GNG), de novo and salvage synthesis of purine/pyrimidine nucleotides, and ADP-ribosylation in CA PD-OTC. Altered metabolic activities were in part accountable by expression changes in key enzymes measured by Reverse Phase Protein Array profiling. Notably, Gln-fueled GNG products were preferentially diverted to support purine nucleotide synthesis. When blocking this novel process with an inhibitor of phosphoenolpyruvate carboxykinase (3-mercaptopicolinic acid or 3-MPA), metastatic, ERlow/PR-/HER2- CA OTC displayed compromised cellularity, reduced outgrowth, and disrupted growth/survival-supporting metabolism but the matched NC OTC did not. Thus, our PD-OTC culturing method not only promoted understanding of actual patient's tumor metabolism to uncover viable metabolic targets but also enabled target testing and elucidation of therapeutic efficacy.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"25 1","pages":"108495"},"PeriodicalIF":4.8,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
CMP-sialic acid synthetase in Drosophila requires N-glycosylation of a non-canonical site. 果蝇的cmp -唾液酸合成酶需要非规范位点的n-糖基化。
IF 4.8 2区 生物学
Journal of Biological Chemistry Pub Date : 2025-04-07 DOI: 10.1016/j.jbc.2025.108483
Boris Novikov,Devon J Boland,Ilya Mertsalov,Hilary Scott,Saniya Dauletbayeva,Pedro Monagas-Valentin,Vladislav Panin
{"title":"CMP-sialic acid synthetase in Drosophila requires N-glycosylation of a non-canonical site.","authors":"Boris Novikov,Devon J Boland,Ilya Mertsalov,Hilary Scott,Saniya Dauletbayeva,Pedro Monagas-Valentin,Vladislav Panin","doi":"10.1016/j.jbc.2025.108483","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.108483","url":null,"abstract":"Sialylation plays important roles in animals, affecting numerous molecular and cell interactions. In Drosophila, sialylation regulates neural transmission and mediates communication between neurons and glia. Drosophila CMP-sialic acid synthetase (CSAS), a key enzyme of the sialylation pathway, is localized to the Golgi and modified by N-glycosylation, suggesting that this modification can affect CSAS function. Here we tested this hypothesis using in vitro and in vivo approaches. We found that CSAS proteins from divergent Drosophila species have two conserved N-glycosylation sites, including the rarely glycosylated non-canonical N-X-C sequon. We investigated CSAS glycosylation by generating CSAS \"glycomutants\" lacking glycosylation sites and analyzing them in vivo in transgenic rescue assays. The removal of non-canonical glycosylation significantly decreased CSAS activity, while the canonical site mutation did not affect CSAS function. Although all glycomutants were similarly localized to the Golgi, the non-canonical glycosylation, unlike the canonical one, affected CSAS stability in vivo and in vitro. Our results suggested that CSAS functions as a dimer, which was also supported by protein structure predictions that produced a dimer recapitulating the crystal structures of mammalian and bacterial counterparts, highlighting the evolutionary conservation of the CSAS structure-function relationship. This conclusion was supported by the rescue of CSAS mutants using the human ortholog. The non-canonical CSAS glycosylation was discussed in terms of a potential mechanism of temperature-dependent regulation of sialylation in poikilotherms that modulates neural activity in heat-shock conditions. Taken together, we uncovered an important regulation of sialylation in Drosophila, highlighting a novel interplay between glycosylation pathways in neural regulation.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"112 1","pages":"108483"},"PeriodicalIF":4.8,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Bifunctional compounds for targeted degradation of carbonic anhydrase IX through integrin-facilitated lysosome degradation. 通过整合素促进溶酶体降解靶向降解碳酸酐酶IX的双功能化合物。
IF 4.8 2区 生物学
Journal of Biological Chemistry Pub Date : 2025-04-07 DOI: 10.1016/j.jbc.2025.108482
Wanyi He,Congli Chen,Runjie Cai,Jiwei Zheng,Mengyu Yao,Joong Sup Shim,Hang Fai Kwok,Xiaojun Yao,Lijing Fang,Liang Chen
{"title":"Bifunctional compounds for targeted degradation of carbonic anhydrase IX through integrin-facilitated lysosome degradation.","authors":"Wanyi He,Congli Chen,Runjie Cai,Jiwei Zheng,Mengyu Yao,Joong Sup Shim,Hang Fai Kwok,Xiaojun Yao,Lijing Fang,Liang Chen","doi":"10.1016/j.jbc.2025.108482","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.108482","url":null,"abstract":"As an important therapeutic target, carbonic anhydrase IX (CAIX) is crucial in pH regulation of hypoxic solid tumors, thus keeping the survival of them in acidic microenvironment, and promoting their proliferation, invasion and metastasis. To degrade endogenous CAIX, three bifunctional compounds were designed according to the integrin-facilitated lysosomal degradation (IFLD) strategy. These compounds are composed of a CAIX binding ligand, an integrin-recognizing ligand, connected via a linker, which could induce CAIX degradation in an integrin- and lysosome-dependent manner. Among them, Sul-L1-RGD showed the highest degradation efficacy, and could inhibit the proliferation of tumor cells under hypoxic conditions, thus it has great potential to be applied in cancer drug discovery.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"39 1","pages":"108482"},"PeriodicalIF":4.8,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Spectral flow cytometry for detecting DNA cargo in malaria parasite-derived extracellular vesicles. 光谱流式细胞术检测疟疾寄生虫来源的细胞外囊泡中的DNA货物。
IF 4 2区 生物学
Journal of Biological Chemistry Pub Date : 2025-04-06 DOI: 10.1016/j.jbc.2025.108481
Ewa Kozela, Ekaterina Petrovich-Kopitman, Yuval Berger, Abel Cruz Camacho, Yaara Shoham, Mattia I Morandi, Irit Rosenhek-Goldian, Ron Rotkopf, Neta Regev-Rudzki
{"title":"Spectral flow cytometry for detecting DNA cargo in malaria parasite-derived extracellular vesicles.","authors":"Ewa Kozela, Ekaterina Petrovich-Kopitman, Yuval Berger, Abel Cruz Camacho, Yaara Shoham, Mattia I Morandi, Irit Rosenhek-Goldian, Ron Rotkopf, Neta Regev-Rudzki","doi":"10.1016/j.jbc.2025.108481","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.108481","url":null,"abstract":"<p><p>Cells across biological kingdoms release extracellular vesicles (EVs) as a means of communication with other cells, be their friends or foes. This is indeed true for the intracellular malaria parasite Plasmodium falciparum (Pf), which utilizes EVs to transport bioactive molecules to various human host systems. Yet, the study of this mode of communication in malaria research is currently constrained due to limitations in high-resolution tools and the absence of commercial antibodies. Here, we demonstrate the power of an advanced spectral flow cytometry approach to robustly detect secreted EVs, isolated from Pf-infected red blood cells. By labeling both EV membrane lipids and the DNA cargo within (non-antibody staining approach), we were able to detect a subpopulation of parasitic-derived EVs enriched in DNA. Furthermore, we could quantitatively measure the DNA-carrying EVs isolated from two distinct blood stages of the parasite: rings and trophozoites. Our findings showcase the potential of spectral flow cytometry to monitor dynamic changes in nucleic acid cargo within pathogenic EVs.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108481"},"PeriodicalIF":4.0,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Cyclosporine A sterically inhibits statin transport by solute carrier OATP1B1. 环孢素A通过溶质载体OATP1B1立体抑制他汀类药物的转运。
IF 4 2区 生物学
Journal of Biological Chemistry Pub Date : 2025-04-06 DOI: 10.1016/j.jbc.2025.108484
Min Woo Sung, Kuan Hu, Lea M Hurlimann, Joshua A Lees, Kimberly F Fennell, Mark A West, Chester Costales, Amilcar David Rodrigues, Iwan Zimmermann, Roger J P Dawson, Shenping Liu, Seungil Han
{"title":"Cyclosporine A sterically inhibits statin transport by solute carrier OATP1B1.","authors":"Min Woo Sung, Kuan Hu, Lea M Hurlimann, Joshua A Lees, Kimberly F Fennell, Mark A West, Chester Costales, Amilcar David Rodrigues, Iwan Zimmermann, Roger J P Dawson, Shenping Liu, Seungil Han","doi":"10.1016/j.jbc.2025.108484","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.108484","url":null,"abstract":"<p><p>Members of the Organic Anion Transporter Polypeptides (OATP) are integral membrane proteins responsible for facilitating the transport of organic anions across the cell membrane. OATP1B1 (SLCO1B1), the prototypic OATP family member, is the most abundant uptake transporter in the liver and key mediator of the hepatic uptake and clearance of numerous endogenous and xenobiotic compounds. It serves as a locus of important drug-drug interactions, such as those between statins and cyclosporine A, and carries the potential to enable liver-targeting therapeutics. In this study, we report cryo-EM structures of OATP1B1 and its complexes with one of its statin substrates, atorvastatin, and an inhibitor, cyclosporine A. This structural analysis has yielded insights into the mechanisms underlying OATP1B1-mediated transport of statins and the inhibitory effect of cyclosporine A. These findings contribute to a better understanding of the molecular processes involved in drug transport and offer potential avenues for the development of targeted medications for liver-related conditions.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108484"},"PeriodicalIF":4.0,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The evolution of AKAPs and emergence of PKA isotype selective anchoring determinants. akap的进化和PKA同型选择性锚定决定因子的出现。
IF 4 2区 生物学
Journal of Biological Chemistry Pub Date : 2025-04-06 DOI: 10.1016/j.jbc.2025.108480
Jerome I Falcone, Kristan H Cleveland, Mingu Kang, Brianna J Odle, Katherine A Forbush, John D Scott
{"title":"The evolution of AKAPs and emergence of PKA isotype selective anchoring determinants.","authors":"Jerome I Falcone, Kristan H Cleveland, Mingu Kang, Brianna J Odle, Katherine A Forbush, John D Scott","doi":"10.1016/j.jbc.2025.108480","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.108480","url":null,"abstract":"<p><p>Cyclic AMP is a versatile signaling molecule utilized throughout the eukaryotic domain. A frequent use is to activate protein kinase A (PKA), a serine/threonine kinase that drives many physiological responses. Spatiotemporal organization of PKA occurs though association with A-kinase anchoring proteins (AKAPs). Sequence alignments and phylogenetic analyses trace the evolution of PKA regulatory (R) and catalytic (C) subunits, and AKAPs from the emergence of metazoans. AKAPs that preferentially associate with the type I (RI), or type II (RII) regulatory subunits diverged at the advent of the vertebrate clade. Type I PKA anchoring proteins including smAKAP contain an FA motif at positions 1 and 2 of their amphipathic binding helices. Fluorescence recovery after photobleaching (FRAP) measurements indicate smAKAP preferentially associates with RI (T 1/2. 4.37 ± 1.2 sec; n=3) as compared to RII (T 1/2. 2.19 ± 0.5 sec; n=3). Parallel studies measured AKAP79 recovery half times of 8.74 ± 0.3 sec (n=3) for RI and 14.42 ± 2.1 sec (n=3) and for RII respectively. Introduction of FA and AF motifs at either ends of the AKAP79 helix biases the full length anchoring protein toward type I PKA signaling to reduce corticosterone release from adrenal cells by 61.5 ± 0.8 % (n=3). Conversely, substitution of the YA motif at the beginning of the smAKAP helix for a pair of leucine's abrogates RI anchoring. Thus, AKAPs have evolved from the base of the metazoan clade into specialized type I and type II PKA anchoring proteins.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108480"},"PeriodicalIF":4.0,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
YTHDF2 Suppresses the 2C-like State in Mouse Embryonic Stem Cells via the DUX-ZSCAN4 Molecular Circuit. YTHDF2通过DUX-ZSCAN4分子电路抑制小鼠胚胎干细胞2c样状态
IF 4 2区 生物学
Journal of Biological Chemistry Pub Date : 2025-04-04 DOI: 10.1016/j.jbc.2025.108479
Xiang Wu, Wanting Cai, Junjie He, Shiyin Zhang, Shen Wang, Lingci Huang, Haotian Zhang, Xiaoyan Sun, Jun Zhou, Xiao-Min Liu
{"title":"YTHDF2 Suppresses the 2C-like State in Mouse Embryonic Stem Cells via the DUX-ZSCAN4 Molecular Circuit.","authors":"Xiang Wu, Wanting Cai, Junjie He, Shiyin Zhang, Shen Wang, Lingci Huang, Haotian Zhang, Xiaoyan Sun, Jun Zhou, Xiao-Min Liu","doi":"10.1016/j.jbc.2025.108479","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.108479","url":null,"abstract":"<p><p>Mouse embryonic stem cells (ESCs) consist of a rare population of heterogeneous 2-cell-like cells (2CLCs). These cells transiently recapitulate the transcriptional and epigenetic features of the 2-cell embryos, serving as a unique model for studying totipotency acquisition and embryonic development. Accumulating evidence has demonstrated that transcription factors and epigenetic modifications exert crucial functions in the transition of ESCs to 2CLCs. However, the roles of RNA modification in the regulation of 2C-like state remain elusive. Using DUX-induced 2CLCs system, we examine N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) modification landscape in transcriptome-wide, and observe dynamic regulation of m<sup>6</sup>A during DUX-driven 2C-like reprogramming. Notably, many core 2C transcripts like Dux and Zscan4, are highly methylated. We identify the m<sup>6</sup>A reader protein YTHDF2 as a critical regulator of 2C-like state. Depletion of YTHDF2 facilitates robust expressions of 2C-signature genes and ESCs-to-2CLCs transition. Intriguingly, YTHDF2 binds to a subset of m<sup>6</sup>A-modified 2C transcripts and promotes their decay. We further demonstrate that YTHDF2 suppresses the 2C-like program in a manner that is dependent on both m<sup>6</sup>A and the DUX-ZSCAN4 molecular circuit. Mechanistically, YTHDF2 interacts with CNOT1, a key component of RNA deadenylase complex. Consistently, silencing of CNOT1 upregulates the 2C program and promotes ESCs-to-2CLCs transition. Collectively, our findings reveal novel insights into the epitranscriptomic regulation of the 2C-like state in mouse ESCs.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108479"},"PeriodicalIF":4.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
RIPC improves myocardial injury by promoting mitochondrial protection via the PGC-1α/Nrf2 pathway. RIPC通过PGC-1α/Nrf2途径促进线粒体保护,从而改善心肌损伤。
IF 4 2区 生物学
Journal of Biological Chemistry Pub Date : 2025-04-04 DOI: 10.1016/j.jbc.2025.108476
Zhenzhou Zhao, Zhiwen Zhang, Xuejie Li, Jiaxing Ding, Muwei Li
{"title":"RIPC improves myocardial injury by promoting mitochondrial protection via the PGC-1α/Nrf2 pathway.","authors":"Zhenzhou Zhao, Zhiwen Zhang, Xuejie Li, Jiaxing Ding, Muwei Li","doi":"10.1016/j.jbc.2025.108476","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.108476","url":null,"abstract":"<p><p>Myocardial infarction (MI) is a common condition with high morbidity and mortality rates. Remote ischemic preconditioning (RIPC) activates the endogenous protective mechanisms by promoting ischemic tolerance and mitigating the subsequent damage caused by fatal ischemia. Maintaining mitochondrial function is imperative for the prevention of myocardial ischemia. The current study aims to evaluate the therapeutic effects of RIPC on MI with a focus on the mechanisms involved in mitochondrial function. In our study, patients with MI who underwent coronary angiography were randomly assigned to either the RIPC group (n = 20) or the control group (n = 20). RIPC intervention was administered preoperatively by inflating a blood pressure cuff on the upper arm to 200 mmHg for four cycles of 5 min each, interspersed with 5-min reperfusion intervals. The process alleviated myocardial injury among the participants, accompanied by a significant elevation in the serum concentrations of PGC-1α and Nrf2 levels in the serum. In-vitro studies showed that RIPC can protect cardiomyocytes against ischemic injury by preserving the mitochondrial morphology, maintaining mitochondrial membrane integrity, and reducing oxidative stress. In-vivo experimental findings illustrated that RIPC mitigated myocardial structural damage in mice by augmenting mitochondrial function, leading to significant cardiac protection, as evidenced by improved cardiac function and reduced infarct size. Moreover, the protective effects of RIPC were abolished upon silencing of PGC-1α. Collectively, the results indicated that RIPC activates the PGC-1α/Nrf2 signaling pathway to rescue cardiomyocytes by maintaining mitochondrial function during ischemic insult, suggesting a promising strategy for preventing cardiac ischemia injury.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108476"},"PeriodicalIF":4.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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