The idea of mRNA therapy had been conceived for decades before it came into reality during the Covid-19 pandemic.The mRNA vaccine emerges as a powerful and general tool against new viral infections,largely due to its ...The idea of mRNA therapy had been conceived for decades before it came into reality during the Covid-19 pandemic.The mRNA vaccine emerges as a powerful and general tool against new viral infections,largely due to its versatility and rapid development.In addition to prophylactic vaccines,mRNA technology also offers great promise for new applications as a versatile drug modality.However,realizing the conceptual potential faces considerable challenges,such as minimal immune stimulation,high and long-term expression,and efficient delivery to target cells and tissues.Here we review the applications of mRNA-based therapeutics,with emphasis on the innovative design and future challenges/solutions.In addition,we also discuss the next generation of mRNA therapy,including circular mRNA and self-amplifying RNAs.We aim to provide a conceptual overview and outlook on mRNA therapeutics beyond prophylactic vaccines.展开更多
Thousands of proteins undergo arginine methylation,a widespread post-translational modification catalyzed by several protein arginine methyltransferases(PRMTs).However,global understanding of their biological function...Thousands of proteins undergo arginine methylation,a widespread post-translational modification catalyzed by several protein arginine methyltransferases(PRMTs).However,global understanding of their biological functions is limited due to the lack of a complete picture of the catalytic network for each PRMT.Here,we systematically identified interacting proteins for all human PRMTs and demonstrated their functional importance in mRNA splicing and translation.We demonstrated significant overlapping of interactomes of human PRMTs with the known methylarginine-containing proteins.Different PRMTs are functionally redundant with a high degree of overlap in their substrates and high similarities between their putative methylation motifs.Importantly,RNA-binding proteins involved in regulating RNA splicing and translation contain highly enriched arginine methylation regions.Moreover,inhibition of PRMTs globally alternates alternative splicing(AS)and suppresses translation.In particular,ribosomal proteins are extensively modified with methylarginine,and mutations in their methylation sites suppress ribosome assembly,translation,and eventually cell growth.Collectively,our study provides a global view of different PRMT networks and uncovers critical functions of arginine methylation in regulating mRNA splicing and translation.展开更多
基金the National Natural Science Foundation of China(NSFC)to Z.W.(91940303 and 31730110)and H-H W.(32171294)the Science and Technology Commission of Shanghai Municipality(STCSM)to H-H W.(20ZR1467300)+1 种基金the National Key Research and Development Program of China(2021YFA1300503)Z.W.Z.W.is also sponsored by the type A CAS Pioneer 100-Talent program,and the Starry Night Science Fund at Shanghai Institute for Advanced Study of Zhejiang University(SN-ZJU-SIAS-009).
文摘The idea of mRNA therapy had been conceived for decades before it came into reality during the Covid-19 pandemic.The mRNA vaccine emerges as a powerful and general tool against new viral infections,largely due to its versatility and rapid development.In addition to prophylactic vaccines,mRNA technology also offers great promise for new applications as a versatile drug modality.However,realizing the conceptual potential faces considerable challenges,such as minimal immune stimulation,high and long-term expression,and efficient delivery to target cells and tissues.Here we review the applications of mRNA-based therapeutics,with emphasis on the innovative design and future challenges/solutions.In addition,we also discuss the next generation of mRNA therapy,including circular mRNA and self-amplifying RNAs.We aim to provide a conceptual overview and outlook on mRNA therapeutics beyond prophylactic vaccines.
基金This work was supported by the National Natural Science Foundation of China(31730110,31661143031,91940303,and 91753135)the Science and Technology Commission of Shanghai Municipality grant(17JC1404900,18XD1404400,and 20ZR1467300)a Joint Research grant with State Key Laboratory of Microbial Metabolism,School of Life Science and Biotechnology,Shanghai Jiao Tong University(MMLKF16-11).
文摘Thousands of proteins undergo arginine methylation,a widespread post-translational modification catalyzed by several protein arginine methyltransferases(PRMTs).However,global understanding of their biological functions is limited due to the lack of a complete picture of the catalytic network for each PRMT.Here,we systematically identified interacting proteins for all human PRMTs and demonstrated their functional importance in mRNA splicing and translation.We demonstrated significant overlapping of interactomes of human PRMTs with the known methylarginine-containing proteins.Different PRMTs are functionally redundant with a high degree of overlap in their substrates and high similarities between their putative methylation motifs.Importantly,RNA-binding proteins involved in regulating RNA splicing and translation contain highly enriched arginine methylation regions.Moreover,inhibition of PRMTs globally alternates alternative splicing(AS)and suppresses translation.In particular,ribosomal proteins are extensively modified with methylarginine,and mutations in their methylation sites suppress ribosome assembly,translation,and eventually cell growth.Collectively,our study provides a global view of different PRMT networks and uncovers critical functions of arginine methylation in regulating mRNA splicing and translation.
