Haoxian Zhou, Shu Wu, Bin Li, Rongjinlei Zhang, Ying Zou, Mibu Cao, Anhua Xu, Kewei Zheng, Qinghua Zhou, Jia Wang, Jinping Zheng, Jianhua Yang, Yuanlong Ge, Zhanyi Lin, Zhenyu Ju
Loss of protein homeostasis is a hallmark of cellular senescence, and ribosome pausing plays a crucial role in the collapse of proteostasis. However, our understanding of ribosome pausing in senescent cells remains limited. In this study, we utilized ribosome profiling and G-quadruplex RNA immunoprecipitation sequencing techniques to explore the impact of RNA G-quadruplex (rG4) on the translation efficiency in senescent cells. Our results revealed a reduction in the translation efficiency of rG4-rich genes in senescent cells and demonstrated that rG4 structures within coding sequence can impede translation both in vivo and in vitro. Moreover, we observed a significant increase in the abundance of rG4 structures in senescent cells, and the stabilization of the rG4 structures further exacerbated cellular senescence. Mechanistically, the RNA helicase DHX9 functions as a key regulator of rG4 abundance, and its reduced expression in senescent cells contributing to increased ribosome pausing. Additionally, we also observed an increased abundance of rG4, an imbalance in protein homeostasis, and reduced DHX9 expression in aged mice. In summary, our findings reveal a novel biological role for rG4 and DHX9 in the regulation of translation and proteostasis, which may have implications for delaying cellular senescence and the aging process.
蛋白质稳态的丧失是细胞衰老的一个标志，核糖体暂停在蛋白质稳态的崩溃中起着至关重要的作用。然而，我们对衰老细胞中核糖体暂停的理解仍然有限。在这项研究中，我们利用核糖体分析和g -四重体RNA免疫沉淀测序技术来探索RNA g -四重体（rG4）对衰老细胞翻译效率的影响。我们的研究结果揭示了衰老细胞中富含rG4基因的翻译效率降低，并证明了编码序列（CDS）内的rG4结构可以阻碍体内和体外的翻译。此外，我们观察到衰老细胞中rG4结构的丰度显著增加，rG4结构的稳定化进一步加剧了细胞衰老。从机制上讲，RNA解旋酶DHX9是rG4丰度的关键调节因子，其在衰老细胞中的表达减少有助于增加核糖体暂停。此外，我们还观察到老龄小鼠rG4丰度增加，蛋白质稳态失衡，DHX9表达降低。综上所述，我们的研究结果揭示了rG4和DHX9在调节翻译和蛋白质停滞中的新生物学作用，这可能对延缓细胞衰老和衰老过程具有重要意义。
{"title":"RNA G-quadruplex (rG4) exacerbates cellular senescence by mediating ribosome pausing.","authors":"Haoxian Zhou, Shu Wu, Bin Li, Rongjinlei Zhang, Ying Zou, Mibu Cao, Anhua Xu, Kewei Zheng, Qinghua Zhou, Jia Wang, Jinping Zheng, Jianhua Yang, Yuanlong Ge, Zhanyi Lin, Zhenyu Ju","doi":"10.1093/procel/pwaf047","DOIUrl":"10.1093/procel/pwaf047","url":null,"abstract":"<p><p>Loss of protein homeostasis is a hallmark of cellular senescence, and ribosome pausing plays a crucial role in the collapse of proteostasis. However, our understanding of ribosome pausing in senescent cells remains limited. In this study, we utilized ribosome profiling and G-quadruplex RNA immunoprecipitation sequencing techniques to explore the impact of RNA G-quadruplex (rG4) on the translation efficiency in senescent cells. Our results revealed a reduction in the translation efficiency of rG4-rich genes in senescent cells and demonstrated that rG4 structures within coding sequence can impede translation both in vivo and in vitro. Moreover, we observed a significant increase in the abundance of rG4 structures in senescent cells, and the stabilization of the rG4 structures further exacerbated cellular senescence. Mechanistically, the RNA helicase DHX9 functions as a key regulator of rG4 abundance, and its reduced expression in senescent cells contributing to increased ribosome pausing. Additionally, we also observed an increased abundance of rG4, an imbalance in protein homeostasis, and reduced DHX9 expression in aged mice. In summary, our findings reveal a novel biological role for rG4 and DHX9 in the regulation of translation and proteostasis, which may have implications for delaying cellular senescence and the aging process.</p>","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":" ","pages":"953-967"},"PeriodicalIF":12.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12698187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Correction to: CRISPR/Cas9-mediated gene knockout reveals a guardian role of NF-κB/RelA in maintaining the homeostasis of human vascular cells.","authors":"","doi":"10.1093/procel/pwaf009","DOIUrl":"10.1093/procel/pwaf009","url":null,"abstract":"","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":" ","pages":"997"},"PeriodicalIF":12.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12698183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Correction to: Chemical screen identifies a geroprotective role of quercetin in premature aging.","authors":"","doi":"10.1093/procel/pwaf023","DOIUrl":"10.1093/procel/pwaf023","url":null,"abstract":"","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":" ","pages":"998"},"PeriodicalIF":12.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12698181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fathima Athar, Francesco Morandini, Iqra Fatima, Isabella Silvestri, Sei Joong Kim, Minseon Lee, Xiaoyan Liao, Andrei Sharov, Vladimir Botchkarev, Andrei Seluanov, Vera Gorbunova
{"title":"African spiny mice show resistance to DMBA/TPA-induced squamous carcinogenesis with distinct benign tumor profile.","authors":"Fathima Athar, Francesco Morandini, Iqra Fatima, Isabella Silvestri, Sei Joong Kim, Minseon Lee, Xiaoyan Liao, Andrei Sharov, Vladimir Botchkarev, Andrei Seluanov, Vera Gorbunova","doi":"10.1093/procel/pwaf024","DOIUrl":"10.1093/procel/pwaf024","url":null,"abstract":"","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":" ","pages":"896-904"},"PeriodicalIF":12.8,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12578293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yan Bi, Jindian Hu, Tao Wu, Zhaohui Ouyang, Tan Lin, Jiaxing Sun, Xinbao Zhang, Xiaoyu Xu, Hong Wang, Ke Wei, Shaorong Gao, Yixuan Wang
Human naïve pluripotent stem cells (PSCs) hold great promise for embryonic development studies. Existing induction and culture strategies for these cells, heavily dependent on MEK inhibitors, lead to widespread DNA hypomethylation, aberrant imprinting loss, and genomic instability during extended culture. Here, employing high-content analysis alongside a bifluorescence reporter system indicative of human naïve pluripotency, we screened over 1,600 chemicals and identified seven promising candidates. From these, we developed four optimized media-LAY, LADY, LUDY, and LKPY-that effectively induce and sustain PSCs in the naïve state. Notably, cells reset or cultured in these media, especially in the LAY system, demonstrate improved genome-wide DNA methylation status closely resembling that of pre-implantation counterparts, with partially restored imprinting and significantly enhanced genomic stability. Overall, our study contributes advancements to naïve pluripotency induction and long-term maintenance, providing insights for further applications of naïve PSCs.
{"title":"Optimized derivation and culture system of human naïve pluripotent stem cells with enhanced DNA methylation status and genomic stability.","authors":"Yan Bi, Jindian Hu, Tao Wu, Zhaohui Ouyang, Tan Lin, Jiaxing Sun, Xinbao Zhang, Xiaoyu Xu, Hong Wang, Ke Wei, Shaorong Gao, Yixuan Wang","doi":"10.1093/procel/pwaf053","DOIUrl":"10.1093/procel/pwaf053","url":null,"abstract":"<p><p>Human naïve pluripotent stem cells (PSCs) hold great promise for embryonic development studies. Existing induction and culture strategies for these cells, heavily dependent on MEK inhibitors, lead to widespread DNA hypomethylation, aberrant imprinting loss, and genomic instability during extended culture. Here, employing high-content analysis alongside a bifluorescence reporter system indicative of human naïve pluripotency, we screened over 1,600 chemicals and identified seven promising candidates. From these, we developed four optimized media-LAY, LADY, LUDY, and LKPY-that effectively induce and sustain PSCs in the naïve state. Notably, cells reset or cultured in these media, especially in the LAY system, demonstrate improved genome-wide DNA methylation status closely resembling that of pre-implantation counterparts, with partially restored imprinting and significantly enhanced genomic stability. Overall, our study contributes advancements to naïve pluripotency induction and long-term maintenance, providing insights for further applications of naïve PSCs.</p>","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":" ","pages":"858-872"},"PeriodicalIF":12.8,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12578290/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The heat shock protein 70 (Hsp70) family of molecular chaperones is essential for nearly every cell to support protein homeostasis through folding, signaling, and quality control. Hsp70 functionality critically depends on co-chaperones, including the GrpE-like family of nucleotide exchange factors (NEFs), first identified in Escherichia coli as GrpE. These factors have long been recognized for their ability to catalyze the release of Hsp70 nucleotide and protein substrates, but recent structural and functional studies have revealed that GrpE-like NEFs are more than passive exchange catalysts, instead acting as dynamic regulators that coordinate chaperone activity with cellular stress responses, organelle-specific demands, and allosteric control of substrate binding and release. In this review, we synthesize decades of research on GrpE-like proteins across bacteria and eukaryotes, culminating in high-resolution structures of the human mitochondrial NEF, GrpEL1, in complex with mitochondrial Hsp70. We examine how architectural features of GrpE-like NEFs have evolved to meet specialized demands, such as thermosensing in bacteria, redox-responsive regulation in vertebrates, and coordination of protein import in mitochondria. We further describe how discrete structural domains dynamically control chaperone cycling, including nucleotide and substrate release, and how gene duplication and domain specialization have driven functional diversification in higher eukaryotes. Finally, we highlight emerging evidence linking NEF activity to mitochondrial homeostasis, stress adaptation, and disease, reframing GrpE-like NEFs as tunable regulators rather than static cofactors. This perspective positions them as stress-adaptive control points in proteostasis and offers a conceptual framework for understanding how ancient chaperone systems have evolved to meet the regulatory needs of modern and complex eukaryotic cells.
{"title":"Tuning the Hsp70 chaperone cycle: emerging roles of GrpE-like NEFs in proteostasis and organelle function.","authors":"Marc A Morizono,Tiffany V Safar,Mark A Herzik","doi":"10.1093/procel/pwaf086","DOIUrl":"https://doi.org/10.1093/procel/pwaf086","url":null,"abstract":"The heat shock protein 70 (Hsp70) family of molecular chaperones is essential for nearly every cell to support protein homeostasis through folding, signaling, and quality control. Hsp70 functionality critically depends on co-chaperones, including the GrpE-like family of nucleotide exchange factors (NEFs), first identified in Escherichia coli as GrpE. These factors have long been recognized for their ability to catalyze the release of Hsp70 nucleotide and protein substrates, but recent structural and functional studies have revealed that GrpE-like NEFs are more than passive exchange catalysts, instead acting as dynamic regulators that coordinate chaperone activity with cellular stress responses, organelle-specific demands, and allosteric control of substrate binding and release. In this review, we synthesize decades of research on GrpE-like proteins across bacteria and eukaryotes, culminating in high-resolution structures of the human mitochondrial NEF, GrpEL1, in complex with mitochondrial Hsp70. We examine how architectural features of GrpE-like NEFs have evolved to meet specialized demands, such as thermosensing in bacteria, redox-responsive regulation in vertebrates, and coordination of protein import in mitochondria. We further describe how discrete structural domains dynamically control chaperone cycling, including nucleotide and substrate release, and how gene duplication and domain specialization have driven functional diversification in higher eukaryotes. Finally, we highlight emerging evidence linking NEF activity to mitochondrial homeostasis, stress adaptation, and disease, reframing GrpE-like NEFs as tunable regulators rather than static cofactors. This perspective positions them as stress-adaptive control points in proteostasis and offers a conceptual framework for understanding how ancient chaperone systems have evolved to meet the regulatory needs of modern and complex eukaryotic cells.","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":"1 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fibrosis, resulting from excess extracellular matrix (ECM) deposition, is a feature of adipose tissue (AT) dysfunction and obesity-related insulin resistance. Emerging evidence indicates that adipogenic stem and precursor cells (ASPCs) are a crucial origin of ECM proteins and possess the potential to induce AT fibrosis. Here, we employed single-cell RNA-seq and identified a unique subset of ASPCs that closely associated with ECM function. Within this subset, we discerned a notable upregulation in the expression of Fibulin-7 (FBLN7), a secreted glycoprotein, in obese mice. Similarly, in humans, FBLN7 levels exhibited an increase in visceral fat among obese individuals and demonstrated a correlation with clinical metabolic traits. Functional studies further revealed that, in response to caloric excess, ASPCs-specific FBLN7 knockout mice display a diminished state of AT fibrosis-inflammation, along with improved systemic metabolic health. Notably, the depletion of FBLN7 in ASPCs suppressed TGF-β-induced fibrogenic responses, whereas its overexpression amplified such responses. Mechanistically, FBLN7 interacted with thrombospondin-1 (TSP1) via its EGF-like calcium-binding domain, thereby enhancing the stability of the TSP1 protein. This, in turn, facilitated the conversion of latent TGF-β to its bio-active form, subsequently promoting TGFBR1/Smad signaling pathways. Furthermore, we developed an anti-FBLN7 neutralizing antibody, which could dramatically alleviate diet-induced AT fibrosis. These results suggest that FBLN7, produced by ASPCs, exerts a major influence in the development of AT fibrosis and may represent a potential target for therapeutic intervention.
{"title":"Fibulin-7 in progenitor cells promotes adipose tissue fibrosis and disrupts metabolic homeostasis in obesity.","authors":"Hairong Yu,Fan Yang,Dandan Yan,Wei Chen,Lijun Yao,Hongli Chen,Siyu Lai,Jinyin Zha,Yi Sun,Yicen Zong,Jian Yu,Hong Zhang,Feng Jiang,Rong Zhang,Jian Zhang,Jing Yan,Cheng Hu","doi":"10.1093/procel/pwaf084","DOIUrl":"https://doi.org/10.1093/procel/pwaf084","url":null,"abstract":"Fibrosis, resulting from excess extracellular matrix (ECM) deposition, is a feature of adipose tissue (AT) dysfunction and obesity-related insulin resistance. Emerging evidence indicates that adipogenic stem and precursor cells (ASPCs) are a crucial origin of ECM proteins and possess the potential to induce AT fibrosis. Here, we employed single-cell RNA-seq and identified a unique subset of ASPCs that closely associated with ECM function. Within this subset, we discerned a notable upregulation in the expression of Fibulin-7 (FBLN7), a secreted glycoprotein, in obese mice. Similarly, in humans, FBLN7 levels exhibited an increase in visceral fat among obese individuals and demonstrated a correlation with clinical metabolic traits. Functional studies further revealed that, in response to caloric excess, ASPCs-specific FBLN7 knockout mice display a diminished state of AT fibrosis-inflammation, along with improved systemic metabolic health. Notably, the depletion of FBLN7 in ASPCs suppressed TGF-β-induced fibrogenic responses, whereas its overexpression amplified such responses. Mechanistically, FBLN7 interacted with thrombospondin-1 (TSP1) via its EGF-like calcium-binding domain, thereby enhancing the stability of the TSP1 protein. This, in turn, facilitated the conversion of latent TGF-β to its bio-active form, subsequently promoting TGFBR1/Smad signaling pathways. Furthermore, we developed an anti-FBLN7 neutralizing antibody, which could dramatically alleviate diet-induced AT fibrosis. These results suggest that FBLN7, produced by ASPCs, exerts a major influence in the development of AT fibrosis and may represent a potential target for therapeutic intervention.","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":"68 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lingxue Niu,Zhenqiang Deng,Yiyu Jin,Ningzi Guan,Haifeng Ye
Engineered oncolytic bacteria are emerging as a promising platform for precision cancer therapy, combining inherent tumor tropism, immunogenicity, and programmable gene control. Advances in synthetic biology now enable inducible and autonomous circuits that sense exogenous inputs (chemical signals or physical signals), bacterial self-cues (quorum sensing, bacterial invasion switches, or nitric oxide-responsive promoters), and tumor-specific pathophysiology (hypoxia, low pH, or lactate). These designs regulate colonization, lysis, and the spatiotemporally confined release of therapeutic cargos-including prodrug-converting enzymes, cytokines, and antibody/nanobody fragments-thereby enhancing antitumor efficacy while limiting off-target toxicity. Beyond monotherapy, oncolytic bacteria integrate with complementary modalities-including immune-checkpoint blockade, adoptive cell therapies (CAR-T/NK), radiotherapy/chemotherapy, nanomedicine, and oncolytic viruses-to amplify immune activation and to enable multimodal, synergistic regimens. Concurrently, biosensor modules transform bacterial chassis into programmable "microbial factories" that couple therapy with real-time imaging and adaptive responses within the tumor microenvironment. This review synthesizes design principles for bacterial gene regulation, surveys recent preclinical advances, and highlights emerging combination strategies, while outlining translational considerations for safety, manufacturability, and dosing, and patient selection. Together, these developments position engineered oncolytic bacteria as a promising route toward safe, effective, and ultimately personalized bacteria-based cancer therapeutics.
{"title":"Engineering oncolytic bacteria as precision cancer therapeutics: design principles, therapeutic strategies, and translational perspectives.","authors":"Lingxue Niu,Zhenqiang Deng,Yiyu Jin,Ningzi Guan,Haifeng Ye","doi":"10.1093/procel/pwaf085","DOIUrl":"https://doi.org/10.1093/procel/pwaf085","url":null,"abstract":"Engineered oncolytic bacteria are emerging as a promising platform for precision cancer therapy, combining inherent tumor tropism, immunogenicity, and programmable gene control. Advances in synthetic biology now enable inducible and autonomous circuits that sense exogenous inputs (chemical signals or physical signals), bacterial self-cues (quorum sensing, bacterial invasion switches, or nitric oxide-responsive promoters), and tumor-specific pathophysiology (hypoxia, low pH, or lactate). These designs regulate colonization, lysis, and the spatiotemporally confined release of therapeutic cargos-including prodrug-converting enzymes, cytokines, and antibody/nanobody fragments-thereby enhancing antitumor efficacy while limiting off-target toxicity. Beyond monotherapy, oncolytic bacteria integrate with complementary modalities-including immune-checkpoint blockade, adoptive cell therapies (CAR-T/NK), radiotherapy/chemotherapy, nanomedicine, and oncolytic viruses-to amplify immune activation and to enable multimodal, synergistic regimens. Concurrently, biosensor modules transform bacterial chassis into programmable \"microbial factories\" that couple therapy with real-time imaging and adaptive responses within the tumor microenvironment. This review synthesizes design principles for bacterial gene regulation, surveys recent preclinical advances, and highlights emerging combination strategies, while outlining translational considerations for safety, manufacturability, and dosing, and patient selection. Together, these developments position engineered oncolytic bacteria as a promising route toward safe, effective, and ultimately personalized bacteria-based cancer therapeutics.","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":"140 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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