Eukaryotic initiation factor 4 A(eIF4A)plays critical roles during translation initiation of cellular mRNAs by forming the cap-binding eIF4F complex,recruiting the 40S small ribosome subunit,and scanning the 5’untran...Eukaryotic initiation factor 4 A(eIF4A)plays critical roles during translation initiation of cellular mRNAs by forming the cap-binding eIF4F complex,recruiting the 40S small ribosome subunit,and scanning the 5’untranslated region(5’UTR)for the start codon.eIF4A1 and eIF4A2,two isoforms of eIF4A,are highly conserved and exchange freely within eIF4F complexes.The understanding of their biological and molecular functions remains incomplete if not fragmentary.In this study,we showed that eIF4A1 and eIF4A2 exhibit different expression patterns during B-cell development and activation.Mouse genetic analyses showed that they play critical but differential roles during B-cell development and humoral immune responses.While eIF4A1 controls global protein synthesis,eIF4A2 regulates the biogenesis of 18S ribosomal RNA and the 40S ribosome subunit.This study demonstrates the distinct cellular and molecular functions of eIF4A1 and eIF4A2 and reveals a new role of eIF4A2 in controlling 40S ribosome biogenesis.展开更多
Upon recognition of foreign antigens,naïve B cells undergo rapid activation,growth,and proliferation.How B-cell growth and proliferation are coupled with activation remains poorly understood.Combining CRISPR/Cas9...Upon recognition of foreign antigens,naïve B cells undergo rapid activation,growth,and proliferation.How B-cell growth and proliferation are coupled with activation remains poorly understood.Combining CRISPR/Cas9-mediated functional analysis and mouse genetics approaches,we found that Dhx33,an activation-induced RNA helicase,plays a critical role in coupling B-cell activation with growth and proliferation.Mutant mice with B-cell-specific deletion of Dhx33 exhibited impaired B-cell development,germinal center reactions,plasma cell differentiation,and antibody production.Dhx33-deficient B cells appeared normal in the steady state and early stage of activation but were retarded in growth and proliferation.Mechanistically,Dhx33 played an indispensable role in activation-induced upregulation of ribosomal DNA(rDNA)transcription.In the absence of Dhx33,activated B cells were compromised in their ability to ramp up 47S ribosomal RNA(rRNA)production and ribosome biogenesis,resulting in nucleolar stress,p53 accumulation,and cellular death.Our findings demonstrate an essential role for Dhx33 in coupling B-cell activation with growth and proliferation and suggest that Dhx33 inhibition is a potential therapy for lymphoma and antibody-mediated autoimmune diseases.展开更多
基金supported by the National Natural Science Foundation of China(81830047 and 81961138008 to C.X.,31770950 and 32070877 to W.-H.L.)Sanofi Institute for Biomedical Research(SIBR)。
文摘Eukaryotic initiation factor 4 A(eIF4A)plays critical roles during translation initiation of cellular mRNAs by forming the cap-binding eIF4F complex,recruiting the 40S small ribosome subunit,and scanning the 5’untranslated region(5’UTR)for the start codon.eIF4A1 and eIF4A2,two isoforms of eIF4A,are highly conserved and exchange freely within eIF4F complexes.The understanding of their biological and molecular functions remains incomplete if not fragmentary.In this study,we showed that eIF4A1 and eIF4A2 exhibit different expression patterns during B-cell development and activation.Mouse genetic analyses showed that they play critical but differential roles during B-cell development and humoral immune responses.While eIF4A1 controls global protein synthesis,eIF4A2 regulates the biogenesis of 18S ribosomal RNA and the 40S ribosome subunit.This study demonstrates the distinct cellular and molecular functions of eIF4A1 and eIF4A2 and reveals a new role of eIF4A2 in controlling 40S ribosome biogenesis.
基金the National Natural Science Foundation of China(31570882,31770950 and 32070877 to W-H.L,and 81961138008 to CX)the Fundamental Research Funds for the Central Universities of China-Xiamen University(20720170064 to CX)the Sanofi Institute for Biomedical Research(SIBR).
文摘Upon recognition of foreign antigens,naïve B cells undergo rapid activation,growth,and proliferation.How B-cell growth and proliferation are coupled with activation remains poorly understood.Combining CRISPR/Cas9-mediated functional analysis and mouse genetics approaches,we found that Dhx33,an activation-induced RNA helicase,plays a critical role in coupling B-cell activation with growth and proliferation.Mutant mice with B-cell-specific deletion of Dhx33 exhibited impaired B-cell development,germinal center reactions,plasma cell differentiation,and antibody production.Dhx33-deficient B cells appeared normal in the steady state and early stage of activation but were retarded in growth and proliferation.Mechanistically,Dhx33 played an indispensable role in activation-induced upregulation of ribosomal DNA(rDNA)transcription.In the absence of Dhx33,activated B cells were compromised in their ability to ramp up 47S ribosomal RNA(rRNA)production and ribosome biogenesis,resulting in nucleolar stress,p53 accumulation,and cellular death.Our findings demonstrate an essential role for Dhx33 in coupling B-cell activation with growth and proliferation and suggest that Dhx33 inhibition is a potential therapy for lymphoma and antibody-mediated autoimmune diseases.
