The error-prone V(D)J recombination process generates considerable amounts of nonproductive immunoglobulin(Ig)pre-mRNAs.We recently demonstrated that aberrant Ig chains lacking variable(V)domains can be produced after...The error-prone V(D)J recombination process generates considerable amounts of nonproductive immunoglobulin(Ig)pre-mRNAs.We recently demonstrated that aberrant Ig chains lacking variable(V)domains can be produced after nonsense-associated altered splicing(NAS)events.Remarkably,the expression of these truncated Ig polypeptides heightens endoplasmic reticulum stress and shortens plasma cell(PC)lifespan.Many questions remain regarding the molecular mechanisms underlying this new truncated Ig exclusion(TIE-)checkpoint and its restriction to the ultimate stage of B-cell differentiation.To address these issues,we evaluated the extent of NAS of Ig pre-mRNAs using an Ig heavy chain(IgH)knock-in model that allows for uncoupling of V exon skipping from TIE-induced apoptosis.We found high levels of V exon skipping in PCs compared with B cells,and this skipping was correlated with a biallelic boost in IgH transcription during PC differentiation.Chromatin analysis further revealed that the skipped V exon turned into a pseudo-intron.Finally,we showed that hypertranscription of Ig genes facilitated V exon skipping upon passive administration of splice-switching antisense oligonucleotides(ASOs).Thus,V exon skipping is coupled to transcription and increases as PC differentiation proceeds,likely explaining the late occurrence of the TIE-checkpoint and opening new avenues for ASO-mediated strategies in PC disorders.展开更多
基金supported by grants from Fondation ARC(PJA 20161204724/PGA120150202338)INCa(PLBIO15-256)+3 种基金ANR(2017-CE15-0024-01)Ligue Contre le Cancer(comites Correze,Haute-Vienne)Fondation Française pour la Recherche contre le Myelome et les Gammapathies monoclonales(FFRMG)Comited’Organisation de la Recherche sur le Cancer du Limousin(CORC).
文摘The error-prone V(D)J recombination process generates considerable amounts of nonproductive immunoglobulin(Ig)pre-mRNAs.We recently demonstrated that aberrant Ig chains lacking variable(V)domains can be produced after nonsense-associated altered splicing(NAS)events.Remarkably,the expression of these truncated Ig polypeptides heightens endoplasmic reticulum stress and shortens plasma cell(PC)lifespan.Many questions remain regarding the molecular mechanisms underlying this new truncated Ig exclusion(TIE-)checkpoint and its restriction to the ultimate stage of B-cell differentiation.To address these issues,we evaluated the extent of NAS of Ig pre-mRNAs using an Ig heavy chain(IgH)knock-in model that allows for uncoupling of V exon skipping from TIE-induced apoptosis.We found high levels of V exon skipping in PCs compared with B cells,and this skipping was correlated with a biallelic boost in IgH transcription during PC differentiation.Chromatin analysis further revealed that the skipped V exon turned into a pseudo-intron.Finally,we showed that hypertranscription of Ig genes facilitated V exon skipping upon passive administration of splice-switching antisense oligonucleotides(ASOs).Thus,V exon skipping is coupled to transcription and increases as PC differentiation proceeds,likely explaining the late occurrence of the TIE-checkpoint and opening new avenues for ASO-mediated strategies in PC disorders.
