INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Shuangping Ma,Xianting Liu,Yiran Qin,Yilong Wang,Yu Feng,Binfeng Cheng,Lei Wang
Sickle cell disease (SCD) and β-thalassemia are autosomal recessive genetic disorders caused by abnormal synthesis of β-globin chains. Reversing the transition of fetal-to-adult hemoglobin after birth shows great potential in the treatment of these disorders. Here, we identified an RNA-binding protein, RBM3, as a novel HbF (HbF, α 2 γ 2 ) suppressor. Specifically, downregulation of RBM3 in the erythroid progenitor cell line HUDEP-2 robustly induced γ-globin expression at both the mRNA and protein levels, with a slight impact on β-globin levels. Conversely, overexpression of RBM3 in HUDEP-2 cells led to a marked reduction in γ-globin expression. According to the previous study, we introduced specific inhibitors targeting FAK and Src to block RBM3 protein synthesis. Surprisingly, treatment with the FAK inhibitor resulted in a significant increase in γ-globin expression, whereas the Src inhibitor had little effect. Mechanistically, RBM3 depletion accelerated the degradation of BCL11A protein at the post-transcriptional level, without affecting its mRNA stability. Moreover, RBM3 silencing restricted the overall translation efficiency while selectively lifting the ratio of γ-globin mRNA in polysomes. Importantly, downregulation of RBM3 did not impair erythropoiesis progression, suggesting a safe and effective therapeutic strategy for SCD and β-thalassemia. Our findings identify RBM3 as a negative regulator of HbF expression and reveal it as a novel molecular target for modulating the fetal-to-adult hemoglobin switch, holding great promise for the treatment of SCD and β-thalassemia.
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高影响因子
Cell Death & Disease
·
2023
·Vol. 14
·期 2
·1-14
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IF 9
Zhang Shouyi,Lv Chengcheng,Niu Yichen,Li Changqi,Li Xiuming,Shang Yu,Zhang Yunchao,Zhang Yue,Zhang Yong,Zeng Yu
Bone metastasis is the most happened metastatic event in prostate cancer (PCa) and needs a large effort in treatment. When PCa metastasizes to the bone, the new microenvironment can induce the epigenome reprogramming and stemness remodeling of cancer cells, thereby increasing the adaptability of cancer cells to the bone microenvironment, and this even leads to the occurrence of secondary tumor metastasis. Our group has previously found that RNA binding motif 3 (RBM3) affects the stem cell-like properties of PCa by interfering with alternative splicing of CD44. However, whether RBM3, as a stress-response protein, can resist microenvironmental remodeling of PCa particularly in bone metastasis remains unknown. By co-culturing PCa cells with osteoblasts to mimic PCa bone metastases, we found that RBM3 upregulates the N6-methyladenosine (m 6 A) methylation on the mRNA of catenin beta 1 (CTNNB1) in a manner dependent on methyltransferase 3 (METTL3), an N6-adenosine-methyltransferase complex catalytic subunit. Consequently, this modification results in a decreased stability of CTNNB1 mRNA and a followed inactivation of Wnt signaling, which ultimately inhibits the stemness remodeling of PCa cells by osteoblasts. Thus, the present study may extend our understanding of the inhibitory role of RBM3 on particularly bone metastasis of PCa.
研究领域:
肿瘤学
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分子生物学
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癌症生物学
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高影响因子
Nature Communications
·
2025
·Vol. 16
·期 1
·1-19
·
IF 15.7
Zhang Min,Zhang Bin,Liu Chengli,Preußner Marco,Ayachit Megha,Li Weiming,Huang Yafei,Liu Deyi,He Quanwei,Emmerichs Ann-Kathrin,Meinke Stefan,Chen Shu,Wang Lin,Zheng Liduan,Li Qiubai,Huang Qin,Haltenhof Tom,Gao Ruoxi,Qin Xianan,Cheng Aifang,Wei Tianzi,Yu Li,Schubert Mario,Gao Xin,Li Mingchang,Heyd Florian
Mammals tightly regulate their core body temperature, yet how cells sense and respond to small temperature changes remains incompletely understood. Here, we discover RNA G-quadruplexes (rG4s) as key thermosensors enriched near splice sites of cold-repressed exons. These thermosensing RNA structures, when stabilized, mask splice sites, reducing exon inclusion. Specifically, rG4s near splice sites of a cold-repressed poison exon in the neuroprotective RBM3 are stabilized at low temperatures, leading to exon exclusion. This enables evasion of nonsense-mediated decay, increasing RBM3 expression at cold. Importantly, stabilizing rG4 through increasing intracellular potassium with an FDA-approved potassium channel blocker, mimics the hypothermic effect on alternative splicing, thereby increasing RBM3 expression, leading to RBM3-dependent neuroprotection in a mouse model of subarachnoid hemorrhage. Our findings unveil a mechanism how mammalian RNAs directly sense temperature and potassium perturbations, integrating them into gene expression programs. This opens new avenues for treating diseases arising from splicing defects and disorders benefiting from therapeutic hypothermia, especially hemorrhagic stroke.
研究领域:
分子生物学
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神经科学
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RNA生物学
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温度生物学
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基因表达调控
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高影响因子
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