Advanced Science
·
2024
·
IF 14.3
Jiankun Zang,Yousheng Wu,Xuanlin Su,Kaiwei Cai,Man Ke,Niu He,Huili Zhu,Zefeng Tan,Jielin Zhu,Wensheng He,Min Peng,Shiqing Zhang,Hongcheng Mai,Anding Xu,Dan Lu
Small extracellular vesicles (sEVs) contain abundant circular RNAs (circRNAs) and are involved in cellular processes, particularly hypoxia. However, the process that packaging of circRNAs into neuronal sEVs under hypoxia is unclear. This study revealed the spatial mechanism of the Fused in Sarcoma protein (FUS) that facilitates the loading of functional circRNAs into sEVs in hypoxia neurons. It is found that FUS translocated from the nucleus to the cytoplasm and is more enriched in hypoxic neuronal sEVs than in normal sEVs. Cytoplasmic FUS formed aggregates with the sEVs marker protein CD63 in cytoplasmic stress granules (SGs) under hypoxic stress. Meanwhile, cytoplasmic FUS recruited of functional cytoplasmic circRNAs to SGs. Upon relief of hypoxic stress and degradation of SGs, cytoplasmic FUS is transported with those circRNAs from SGs to sEVs. Validation of FUS knockout dramatically reduced the recruitment of circRNAs from SGs and led to low circRNA loading in sEVs, which is also confirmed by the accumulation of circRNAs in the cytoplasm. Furthermore, it is showed that the FUS Zf_RanBP domain regulates the transport of circRNAs to sEVs by interacting with hypoxic circRNAs in SGs. Overall, these findings have revealed a FUS-mediated transport mechanism of hypoxia-related cytoplasmic circRNAs loaded into sEVs under hypoxic conditions.
研究领域:
神经科学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
FEBS LETTERS
·
2015
·Vol. 590
·期 1
·22-33
·
IF 3.169
Xue Fu,Xingjie Gao,Lin Ge,Xiaoteng Cui,Chao Su,Wendong Yang,Xiaoming Sun,Wei Zhang,Zhi Yao,Xi Yang,Jie Yang
Malonate, a classic inhibitor of respiratory electron transport chain, induces mitochondrial stress. Stress granules (SGs) are a kind of dynamic foci structure during stress. The study on the connection of mitochondrial stress and SG assembly is still limited. Here, we demonstrated that malonate treatment leads to SG formation and translation inhibition, apart from mitochondrial stress, including enhanced ROS formation, reduced mitochondrial Δψ m and ATP level. The phosphorylation levels of eIF2α and 4EBP1 protein were affected upon mitochondrial dysfunction. However, knockdown of 4EBP1 affected SG formation, rather than eIF2α. In addition, an increase of ATP level under mitochondrial stress enhanced malonate-induced SG aggregation. Overall, malonate stimulation triggers mitochondrial stress and induces the assembly of non-canonical cellular SGs via 4EBP1 pathway.
研究领域:
细胞生物学
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分子生物学
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生物化学
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PubMed
高影响因子
AGING CELL
·
2024
·Vol. 23
·期 3
·e14053
·
IF 8
Ying Huai,Xue Wang,Wenjing Mao,Xuehao Wang,Yipu Zhao,Xiaohua Chu,Qian Huang,Kang Ru,Ling Zhang,Yu Li,Zhihao Chen,Airong Qian
Aging impairs osteoblast function and bone turnover, resulting in age-related bone degeneration. Stress granules (SGs) are membrane-less organelles that assemble in response to stress via the recruitment of RNA-binding proteins (RBPs), and have emerged as a novel mechanism in age-related diseases. Here, we identified HuR as a bone-related RBP that aggregated into SGs and facilitated osteogenesis during aging. HuR-positive SG formation increased during osteoblast differentiation, and HuR overexpression mitigated the reduction in SG formation observed in senescent osteoblasts. Moreover, HuR positively regulated the mRNA stability and expression of its target β-catenin by binding and recruiting β-catenin into SGs. As a potential therapeutic target, HuR activator apigenin (API) enhanced its expression and thus aided osteoblasts differentiation. API treatment increased HuR nuclear export, enhanced the recruitment of β-catenin into HuR-positive SGs, facilitated β-catenin nuclear translocation, and contributed osteogenesis. Our findings highlight the roles of HuR and its SGs in promoting osteogenesis during skeletal aging and lay the groundwork for novel therapeutic strategies against age-related skeletal disorders.
研究领域:
老年学
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分子生物学
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骨生物学
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PubMed
高影响因子
CELL DEATH AND DIFFERENTIATION
·
2024
·
IF 13.7
Cai Jiangxue,Li Chenxuan,Liu Suyuan,Tan Meiling,Sun Yiran,Sun Xiaoxiao,Yang Miaoxin,He Bin
The cellular stress response system in immune cells plays a crucial role in regulating the development of inflammatory diseases. In response to cellular damage or microbial infection, the assembly of the NLRP3 inflammasome induces pyroptosis and the release of inflammatory cytokines. Meanwhile, Angiogenin (Ang)-mediated transfer RNA-derived small RNAs (tsRNAs) promote cell survival under stressful conditions. While both tsRNAs and inflammasomes are induced under stress conditions, the interplay between these two systems and their implications in regulating inflammatory diseases remains poorly understood. In this study, it was demonstrated that Ang deficiency exacerbated sodium arsenite-induced activation of NLRP3 inflammasome and pyroptosis. Moreover, Ang-induced 5′-tsRNAs inhibited NLRP3 inflammasome activation and pyroptosis. Mechanistically, 5′-tsRNAs recruit DDX3X protein into stress granules (SGs), consequently inhibiting the interaction between DDX3X and NLRP3, thus leading to the suppression of NLRP3 inflammasome activation. Furthermore, in vivo results showed that Ang deficiency led to the downregulation of tsRNAs, ultimately leading to an exacerbation of NLRP3 inflammasome-dependent inflammation, including lipopolysaccharide-induced systemic inflammation and type-2 diabetes-related inflammation. Altogether, our study sheds a new light on the role of Ang-induced 5′-tsRNAs in regulating NLRP3 inflammasome activation via SGs, and highlights tsRNAs as a promising target for the treatment of NLRP3 inflammasome-related diseases.
研究领域:
免疫学
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分子生物学
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炎症
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代谢紊乱
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DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2024
·
IF 6.9
Xing Fa-liang,Li Bo-rui,Fang Ying-jin,Liang Chen,Liu Jiang,Wang Wei,Xu Jin,Yu Xian-jun,Qin Yi,Zhang Bo
Pancreatic ductal adenocarcinoma (PDAC) is distinguished by its aggressive malignancy, limited treatment avenues and a tendency towards chemotherapy resistance, underscoring the critical need for advanced research to uncover new therapeutic approaches. Stress granules (SGs) that is implicated in cellular self-protection mechanism, along with its associated family molecules have shown pro-cancer effects and are closely related to tumor chemotherapy resistance. In this study we investigated the relationship between Ras GTPase-activating protein-binding proteins 2 (G3BP2), a core component of SGs, and the malignancy of PDAC as well as its resistance to the chemotherapy drug gemcitabine. Analyzing TCGA dataset revealed that the expression of G3BP1 and G3BP2 was significantly upregulated in PDAC compared with adjacent normal pancreatic tissues, and the high expression of G3BP2 rather than G3BP1 was significantly associated with poorer overall survival (OS) in PDAC patients. We demonstrated that knockdown of G3BP2 inhibited the proliferation and invasion of PANC‐1 and CFPAC-1 cells in vitro and in vivo. By analyzing the differentially expressed genes in G3BP2 knockdown and overexpressed PANC‐1 cells, we identified DKC1 that was associated with RNA stability and regulation as the target of G3BP2. We demonstrated that G3BP2 bound to PDIA3 mRNA and recruited them into SGs, increasing the stability of PDIA3 mRNA and attenuating its translation efficiency, thereby promoting DKC1 expression. Furthermore, DKC1 could bind to hENT mRNA and inhibited its expression, which enhanced gemcitabine resistance of PDAC. Therefore, we propose a novel mechanism wherein G3BP2 facilitates PDAC’s resistance to chemotherapy by modulating PDIA3-DKC1-hENT in a SGs-dependent way, suggesting G3BP2 SGs a protentional therapeutic target for the treatment in PDAC.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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癌症研究
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DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2025
·
IF 9.7
Ruxuan Ma,Liuting Zheng,Han Yu,Da Huo,Huiyue Zhao,Hao Zhang
In recent years, the chiral biological effects of nanomedicines have garnered significant interest. Research has focused on understanding how material chirality affects cellular transcription and metabolism. Stress granules, which are membraneless organelles formed through liquid–liquid phase separation of G3BP1 proteins and related compartments, have been extensively studied and are closely associated with cellular damage repair and metabolism. The role and mechanism of chiral nanomaterials in modulating stress granules remain unclear. This study aimed to investigate the expression and structural characteristics of stress granules under the influence of chiral nanomaterials, both individually and in combination with chemotherapy. A library of chiral ligand-modified materials was constructed, and techniques such as immunofluorescence, live-cell imaging, fluorescence recovery after photobleaching assays, and proximity labeling combined with proteomics analysis were employed. These methods helped identify the protein corona adsorbed on the surface of the nanomaterials and explore their relationship with nanomaterial chirality. The findings suggest that the assembly of stress granules is influenced by chirality and can be regulated by chiral nanomaterials. Additionally, chemotherapy sensitivity in cancer cells was enhanced, and normal cells were protected by leveraging the chiral-dependent modulation of material assembly in stress granules. This study offers insights into the regulation of membraneless cellular structures based on chiral biological effects.
研究领域:
生物物理
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分子生物学
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癌症研究
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材料科学
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细胞生物学
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DOI
PubMed
高影响因子
Cell Reports
·
2025
·
IF 6.9
Ri-Xin Chen,Ao-Tian Mo,Shui-Dan Xu,Jun-Han Wu,Min-Hua Deng,Shu-Huan Xie,Wei-Tao Zhuang,Jin-Ling Duan,Han Yang,Peng Lin,Zhe He,Ji-Ming Tang,Hai-Yu Zhou,Xiao-Song Ben,Gui-Bin Qiao,Dan Xie
RNAs and RNA-binding proteins (RBPs) play crucial roles in stress granule (SG) dynamics, yet the specific interactions between SG-associated circular RNAs (circRNAs) and RBPs in esophageal squamous cell carcinoma (ESCC) remain unclear. In this study, we identified m6A-modified circG3BP1 as a potential prognostic biomarker in ESCC. Under cisplatin-induced stress, IGF2BPs facilitate the m6A-dependent translocation of circG3BP1 to SGs, where it functions as a scaffold to enhance TIAR-CAPRIN1 interactions, thereby promoting SG nucleation. SG formation suppresses the translation of senescence-associated mRNAs, such as p21 , delaying chemotherapy-induced cellular senescence and contributing to cisplatin resistance in ESCC cells. Clinically, elevated circG3BP1 expression is associated with cisplatin resistance in patients with ESCC. These findings reveal a previously uncharacterized m6A-dependent mechanism by which circG3BP1 promotes SG-mediated chemoresistance, providing a promising potential biomarker and therapeutic target for ESCC treatment.
研究领域:
肿瘤学
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分子生物学
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RNA生物学
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转化医学
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表观遗传学
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细胞应激反应
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药理学
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DOI
PubMed
高影响因子
CELL
·
2023
·
IF 64.5
Qinqin Cui,Hongyun Bi,Zhanyun Lv,Qigui Wu,Jianfeng Hua,Bokai Gu,Chanjuan Huo,Mingmin Tang,Yanqin Chen,Chongjiu Chen,Sihan Chen,Xinrui Zhang,Zhangrui Wu,Zhengkai Lao,Nengyin Sheng,Chengyong Shen,Yongdeng Zhang,Zhi-Ying Wu,Zhigang Jin,Peiguo Yang,Huaqing Liu,Jinsong Li,Ge Bai
Summary Complex diseases often involve the interplay between genetic and environmental factors. Charcot-Marie-Tooth type 2 neuropathies (CMT2) are a group of genetically heterogeneous disorders, in which similar peripheral neuropathology is inexplicably caused by various mutated genes. Their possible molecular links remain elusive. Here, we found that upon environmental stress, many CMT2-causing mutant proteins adopt similar properties by entering stress granules (SGs), where they aberrantly interact with G3BP and integrate into SG pathways. For example, glycyl-tRNA synthetase (GlyRS) is translocated from the cytoplasm into SGs upon stress, where the mutant GlyRS perturbs the G3BP-centric SG network by aberrantly binding to G3BP. This disrupts SG-mediated stress responses, leading to increased stress vulnerability in motoneurons. Disrupting this aberrant interaction rescues SG abnormalities and alleviates motor deficits in CMT2D mice. These findings reveal a stress-dependent molecular link across diverse CMT2 mutants and provide a conceptual framework for understanding genetic heterogeneity in light of environmental stress.
研究领域:
神经病学
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分子生物学
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遗传学
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Xiaoxian Hu,Peiye Wu,Yu Zhao,Yun Wang,Zhongrui Li,Chao Han
Photodynamic therapy (PDT) is a minimally invasive treatment technique that combines photosensitizers and light and can selectively exert cytotoxic effects on malignant tumor cells and prevent their metastasis. However, while PDT is effective, it also triggers a tumor cell integrated stress response (ISR) to produce cytoprotective stress granules (SGs), decreasing its therapeutic efficacy. In this study, we designed a nanodrug delivery system capable of inhibiting the ISR to enhance the antitumor effect of PDT. Specifically, the low-toxicity photosensitizer hypericin (HY) and the highly effective SGs inhibitor imatinib (IM) were encapsulated in the HY and IM nanoparticles (HINPs). HY converts oxygen into reactive oxygen species under light conditions, inducing the apoptosis of tumor cells but simultaneously induces the formation of SGs through the eukaryotic initiation factor-2α-dependent pathway, reducing tumor sensitivity to PDT. IM tightly binds to the SGs core protein Ras-GAP SH3 domain binding protein 1 (G3BP1), preventing G3BP1 from forming a complex with ubiquitin-associated protein 2-like protein to inhibit SGs formation; it also inhibits the ATF3/CHOP/GADD34/PP1 negative feedback regulatory signaling axis of ISR, further disrupting tumor cell ISR and enhancing the efficacy of HY PDT. Both in vivo and in vitro experiments confirmed that HINPs have potent antitumor activity, providing a way to improve the antitumor efficacy of PDT.
研究领域:
肿瘤学
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药理学
·
纳米技术
·
细胞生物学
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DOI
高影响因子
Food & Function
·
2023
·Vol. 14
·期 4
·2200-2211
·
IF 6.1
Dongbao Cai,Xusheng Li,Qingjie Xu,Haiwei Li,Ruijing Liu,Jiali Chen,Xinwei Jiang,Jianxia Sun,Caiyong Lai,Weibin Bai
Testicular hyperthermia induced by unhealthy living habits and pathological or occupational factors can cause spermatogenic dysfunction with an outcome of sub-fertility or even infertility. Cyanidin-3-O-glucoside (C3G) is the most typical anthocyanin in foods that has been recognized as an antioxidant with promising protection for male reproduction. However, its specific effect against testicular hyperthermia and the mechanisms involving its primary gastrointestinal metabolite protocatechuic acid (PCA) are still unexplored. In the present study, testicular hyperthermia in mice was established by employing a single hot water bath at 43 °C for 30 min. C3G and PCA were intragastrically given to investigate their prevention ability against heat stress-induced testicular damage. It was found that C3G and PCA restored the external diameter and thickness, and alleviated atrophy and vacuolation of seminiferous tubules. Simultaneously, C3G and PCA enhanced testicular heat stress tolerance through reducing superfluous eIF2α phosphorylation and stress granule formation. C3G and PCA effectively improved the testicular antioxidant system and regulated the IRE1α-XBP1 pathway, contributing to mitigatory spermatogenesis dysfunction and testicular damage. This finding revealed that anthocyanins were the novel compounds for alleviating testicular damage, and provided a reliable theoretical basis for improving male fertility disturbed by heat stress.
研究领域:
生殖生物学
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药理学
·
分子生物学
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DOI
PubMed
高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-13
·
IF 14.7
Zhang Hong,Guo Huazhang,Li Danni,Zhang Yiling,Zhang Shengnan,Kang Wenyan,Liu Cong,Le Weidong,Wang Liang,Li Dan,Dai Bin
TDP-43 is implicated in the dynamic formation of nuclear bodies and stress granules through phase separation. In diseased states, it can further condense into pathological aggregates in the nucleus and cytoplasm, contributing to the onset of amyotrophic lateral sclerosis. In this study, we evaluate the effect of graphene quantum dots (GQDs) with different functional groups on TDP-43’s phase separation and aggregation in various cellular locations. We find that halogen atom-doped GQDs (GQDs-Cl, Cl-GQDs-OH) penetrate the nuclear envelope, inhibiting the assembly of TDP-43 nuclear bodies and stress granules under oxidative stress or hyperosmotic environments, and reduce amyloid aggregates and disease-associated phosphorylation of TDP-43. Mechanistic analysis reveals GQDs-Cl and Cl-GQDs-OH modulate TDP-43 phase separation through hydrophobic and electrostatic interactions. Our findings highlight the potential of GQDs-Cl and Cl-GQDs-OH in modulating nuclear protein condensation and pathological aggregation, offering direction for the innovative design of GQDs to modulate protein phase separation and aggregation.
研究领域:
神经科学
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材料科学
·
生物物理学
·
细胞生物学
·
纳米技术
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2025
·
IF 16
Jia Liu,Liuting Zheng,Xinyue Li,Wei Tang,Manyu Guo,Yuxing Wang,Xiaoqi Tan,Jiajia Chang,Huiyue Zhao,Dongsheng Zhu,Yu-qiang Ma,Da Huo
Understanding the interaction between nanomaterials and cellular structures is crucial for nanoparticle applications in biomedicine. We have identified a subtype of stress granules, called nanomaterial-provoked stress granules (NSGs), induced by gold nanorods (AuNRs). These NSGs differ from traditional SGs in their physical properties and biological functions. Uptake of AuNRs causes reactive oxygen species accumulation and protein misfolding in the cell, leading to NSG formation. Physically, NSGs have a gel-like core and a liquid-like shell, influenced positively by HSP70 and negatively by HSP90 and the ubiquitin-proteasome system. AuNRs promote NSG assembly by interacting with G3BP1, reducing the energy needed for liquid–liquid phase separation (LLPS). NSGs impact cellular functions by affecting mRNA surveillance and activating Adenosine 5′-monophosphate (AMP)-activated protein kinase signaling, crucial for a cellular stress response. Our study highlights the role of LLPS in nanomaterial metabolism and suggests NSGs as potential targets for drug delivery strategies, advancing the field of nanomedicine.
研究领域:
纳米生物技术
·
细胞生物学
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分子生物学
·
生物医学工程
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）