Protein arginine methyltransferase-6 participates in a range of biological functions,particularly RNA processing,transcription,chromatin remodeling,and endosomal trafficking.However,it remains unclear whether protein ...Protein arginine methyltransferase-6 participates in a range of biological functions,particularly RNA processing,transcription,chromatin remodeling,and endosomal trafficking.However,it remains unclear whether protein arginine methyl transferase-6 modifies neuropathic pain and,if so,what the mechanisms of this effect.In this study,protein arginine methyltransferase-6 expression levels and its effect on neuropathic pain were investigated in the spared nerve injury model,chronic constriction injury model and bone cancer pain model,using immunohistochemistry,western blotting,immunoprecipitation,and label-free proteomic analysis.The results showed that protein arginine methyltransferase-6 mostly co-localized withβ-tubulinⅢin the dorsal root ganglion,and that its expression decreased following spared nerve injury,chronic constriction injury and bone cancer pain.In addition,PRMT6 knockout(Prmt6~(-/-))mice exhibited pain hypersensitivity.Furthermore,the development of spared nerve injury-induced hypersensitivity to mechanical pain was attenuated by blocking the decrease in protein arginine methyltransferase-6 expression.Moreover,when protein arginine methyltransferase-6 expression was downregulated in the dorsal root ganglion in mice without spared nerve injury,increased levels of phosphorylated extracellular signal-regulated kinases were observed in the ipsilateral dorsal horn,and the response to mechanical stimuli was enhanced.Mechanistically,protein arginine methyltransferase-6 appeared to contribute to spared nerve injury-induced neuropathic pain by regulating the expression of heterogeneous nuclear ribonucleoprotein-F.Additionally,protein arginine methyltransfe rase-6-mediated modulation of hete rogeneous nuclear ribonucleoprotein-F expression required amino atids 319 to 388,but not classical H3R2 methylation.These findings indicated that protein arginine methyltransferase-6 is a potential therapeutic target fo r the treatment of peripheral neuro pathic pain.展开更多
F-Box蛋白家族是存在于所有真核生物中的一个庞大且多样化的蛋白质家族,可根据蛋白C端二级结构的不同将其分为FBXW、FBXL、FBXO三类。F-Box蛋白可以通过与S期激酶相关蛋白1(S-phase kinase-associated protein 1,SKP1)、cullin 1(CUL1)...F-Box蛋白家族是存在于所有真核生物中的一个庞大且多样化的蛋白质家族,可根据蛋白C端二级结构的不同将其分为FBXW、FBXL、FBXO三类。F-Box蛋白可以通过与S期激酶相关蛋白1(S-phase kinase-associated protein 1,SKP1)、cullin 1(CUL1)、环盒蛋白1(ring-box 1,Rbx1)结合形成SCF复合体发挥E3泛素连接酶功能,可通过泛素-蛋白酶体途径或其他方式特异性识别底物蛋白,参与细胞周期调控、转录调控、细胞凋亡、细胞信号转导等生命活动。大量研究表明F-Box家族蛋白在宿主-病毒相互作用过程中发挥重要功能,作为SCF复合体的底物识别部分,可以与底物结合并使其K48泛素化后转运至蛋白酶体降解。根据降解的底物不同,F-Box家族蛋白一方面可以发挥抗病毒效果,另一方面可以被病毒利用产生免疫逃逸效果。部分F-Box蛋白可以特异性识别干扰素通路相关信号分子并通过泛素-蛋白酶体途径使其降解,从而上调或抑制干扰素信号,调节宿主相关免疫反应;一些F-Box蛋白可以识别病毒蛋白并通过泛素-蛋白酶体途径降解,抑制病毒的复制与传播;此外病毒还可以劫持F-Box蛋白以促使具有免疫功能的宿主蛋白降解,从而产生免疫逃逸效果。目前大量研究针对F-Box家族蛋白开发了数千种抑制剂,但利用F-Box蛋白进行抗病毒药物的研究鲜有报道。F-Box蛋白家族成员众多,其在病毒-宿主相互作用过程中的功能与机制仍需大量探索,并可成为开发抗病毒药物的新方向。展开更多
基金supported by the National Natural Science Foundation of China,Nos.82001178(to LW),81901129(to LH),82001175(to FX)Shanghai Sailing Program,No.20YF1439200(to LW)+1 种基金the Natural Science Foundation of Shanghai,China,No.23ZR1450800(to LH)and the Fundamental Research Funds for the Central Universities,No.YG2023LC15(to ZX)。
文摘Protein arginine methyltransferase-6 participates in a range of biological functions,particularly RNA processing,transcription,chromatin remodeling,and endosomal trafficking.However,it remains unclear whether protein arginine methyl transferase-6 modifies neuropathic pain and,if so,what the mechanisms of this effect.In this study,protein arginine methyltransferase-6 expression levels and its effect on neuropathic pain were investigated in the spared nerve injury model,chronic constriction injury model and bone cancer pain model,using immunohistochemistry,western blotting,immunoprecipitation,and label-free proteomic analysis.The results showed that protein arginine methyltransferase-6 mostly co-localized withβ-tubulinⅢin the dorsal root ganglion,and that its expression decreased following spared nerve injury,chronic constriction injury and bone cancer pain.In addition,PRMT6 knockout(Prmt6~(-/-))mice exhibited pain hypersensitivity.Furthermore,the development of spared nerve injury-induced hypersensitivity to mechanical pain was attenuated by blocking the decrease in protein arginine methyltransferase-6 expression.Moreover,when protein arginine methyltransferase-6 expression was downregulated in the dorsal root ganglion in mice without spared nerve injury,increased levels of phosphorylated extracellular signal-regulated kinases were observed in the ipsilateral dorsal horn,and the response to mechanical stimuli was enhanced.Mechanistically,protein arginine methyltransferase-6 appeared to contribute to spared nerve injury-induced neuropathic pain by regulating the expression of heterogeneous nuclear ribonucleoprotein-F.Additionally,protein arginine methyltransfe rase-6-mediated modulation of hete rogeneous nuclear ribonucleoprotein-F expression required amino atids 319 to 388,but not classical H3R2 methylation.These findings indicated that protein arginine methyltransferase-6 is a potential therapeutic target fo r the treatment of peripheral neuro pathic pain.
