Nature Communications
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2024
·Vol. 15
·期 1
·1-23
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IF 14.7
Luo Yu-Wei,Zhou Jiang-Peng,Ji Hongyu,Xu Doudou,Zheng Anqi,Wang Xin,Dai Zhizheng,Luo Zhicheng,Cao Fang,Wang Xing-Yue,Bai Yunfang,Chen Di,Chen Yueming,Wang Qi,Yang Yaying,Zhang Xinghai,Chiu Sandra,Peng Xiaozhong,Huang Ai-Long,Tang Kai-Fu
Though RNAi and RNA-splicing machineries are involved in regulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication, their precise roles in coronavirus disease 2019 (COVID-19) pathogenesis remain unclear. Herein, we show that decreased RNAi component (Dicer and XPO5) and splicing factor (SRSF3 and hnRNPA3) expression correlate with increased COVID-19 severity. SARS-CoV-2 N protein induces the autophagic degradation of Dicer, XPO5, SRSF3, and hnRNPA3, inhibiting miRNA biogenesis and RNA splicing and triggering DNA damage, proteotoxic stress, and pneumonia. Dicer, XPO5, SRSF3, and hnRNPA3 knockdown increases, while their overexpression decreases, N protein-induced pneumonia’s severity. Older mice show lower expression of Dicer, XPO5, SRSF3, and hnRNPA3 in their lung tissues and exhibit more severe N protein-induced pneumonia than younger mice. PJ34, a poly(ADP-ribose) polymerase inhibitor, or anastrozole, an aromatase inhibitor, ameliorates N protein- or SARS-CoV-2-induced pneumonia by restoring Dicer, XPO5, SRSF3, and hnRNPA3 expression. These findings will aid in developing improved treatments for SARS-CoV-2-associated pneumonia.
研究领域:
分子生物学
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病毒学
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免疫学
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药理学
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病理学
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Cell Death & Disease
·
2025
·Vol. 16
·期 1
·1-19
·
IF 9.6
Chen Shengjun,Wang Yujie,Zhang Jinjin,Liu Bo,Liu Weili,Cao Guohong,Li Rongrong,Li Hongbo,Zhai Nailiang,Song Xiaodong,Zhang Songzi,Lv Changjun
Fibroblast-to-myofibroblast differentiation is the main cytopathologic characteristic of pulmonary fibrosis. However, its underlying molecular mechanism remains poorly understood. This study elucidated that the nuclear export of lncNONMMUT062668.2 (lnc668) exacerbated pulmonary fibrosis by activating fibroblast-to-myofibroblast differentiation. Mechanistic research revealed that histone H3K9 lactylation in the promoter region of the N6-methyladenosine (m 6 A) writer METTL3 was enriched to enhance METTL3 transcription, leading to the lnc668 m 6 A modification. Meanwhile, the m 6 A reader YTHDC1 recognized m 6 A-modified lnc668 and elevated the METTL3-mediated lnc668 modification. Subsequently, phase-separating YTHDC1 promoted the nuclear export of m 6 A-modified lnc668. In this process, the phase-separating YTHDC1 formed a nuclear pore complex with serine/arginine-rich splicing factor 3, Aly/REF export factor, and exportin-5 to assist the translocation of m 6 A-modified lnc668 from nucleus to cytoplasm. After nuclear export, lnc668 facilitated the translation and stability of its host gene phosphatidylinositol-binding clathrin assembly protein to activate fibroblast-to-myofibroblast differentiation, leading to the aggravation of pulmonary fibrosis, which also depended on YTHDC1 phase separation. This study first clarified that YTHDC1 phase separation is crucial for the m 6 A modification, nuclear export, and profibrotic role of lnc668 in exacerbating pulmonary fibrosis. These findings provide new insights into the nuclear export of cytoplasmic lncRNAs and identified potential targets for pulmonary fibrosis therapy.
研究领域:
分子生物学
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表观遗传学
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肺病学
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RNA生物学
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高影响因子
Frontiers in Oncology
·
2025
·
IF 3.3
Zhi-Wen Wang,Hou-Sheng Yang,Hong-Shan Guo,Yue-Ying Li,Jin-Yun Zhong,Shu Jiang,Jia-Peng Li,Zhong-Yi Yang,Chuan-Yi Zhou,Jun Wang,Xing-Hua Liao,Lei Mao
Background Triple-negative breast cancer (TNBC) is the subtype of advanced breast cancer with the shortest survival time and the poorest prognosis, and treatment options are relatively limited. Exosomes, small extracellular vesicles enriched with bioactive molecules, are critical mediators of intercellular communication and have been implicated in cancer progression. The aim of this study was to investigate the molecular mechanism of exosomes promoting the proliferation and migration of TNBC. Methods In this study, exosomes were identified by Flow cytometry and transmission electron microscopy, and RNA sequencing (RNA-seq) was used to identify differentially expressed genes and downstream regulatory molecules in exosomes. RNA-seq results were supported by bioinformatics analysis and Western blot analysis. Functional assays including in vivo tumor formation, Colony formation Assay, Scratch migration and transwell assays were performed to study exosomes related phenomena and mechanism. Results Serum-derived exosomes from patients with TNBC can induce TNBC progression in vitro and in vivo . lncRNA SNHG4 was most significantly up-regulated in exosomes, and overexpression of lncRNA SNHG4 significantly promoted the proliferation and migration of TNBC cells. In addition, lncRNA SNHG4 promotes TNBC cell proliferation and migration by upregulating the expression of Exportin 5(XPO5). Silencing XPO5 can effectively attenuate the tumor-promoting effect of serum exosomes in TNBC patients. Mechanistically, lncRNA SNHG4 acts through XPO5-mediated pathways. Silencing XPO5 can effectively inhibit the tumor-promoting effect mediated by lncRNA SNHG4. Conclusions Taken together, our study revealed that the exosome lncRNA SNHG4 exerts its oncogenic role by activating XPO5-mediated pathways, thereby regulating TNBC cell proliferation and migration. This can be considered as a potential target for TNBC molecular therapy.
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