Physiological and druggable skipping of immunoglobulin variable exons in plasma cells

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...

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Published in:Cellular & molecular immunology Vol. 16; no. 10; pp. 810 - 819
Main Authors: Ashi, Mohamad Omar, Srour, Nivine, Lambert, Jean-Marie, Marchalot, Anne, Martin, Ophélie, Le Noir, Sandrine, Pinaud, Eric, Ayala, Maria Victoria, Sirac, Christophe, Saulière, Jérôme, Moreaux, Jérôme, Cogné, Michel, Delpy, Laurent
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 01-10-2019
Nature Publishing Group
Nature Publishing Group/Chinese Society of Immunology
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Summary: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.
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PMCID: PMC6804933
ISSN:1672-7681
2042-0226
DOI:10.1038/s41423-018-0160-6