Dataset Information

Physiological and druggable skipping of immunoglobulin variable exons in plasma cells.

ABSTRACT: 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.

SUBMITTER: Ashi MO

PROVIDER: S-EPMC6804933 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Physiological and druggable skipping of immunoglobulin variable exons in plasma cells.

Ashi Mohamad Omar MO Srour Nivine N Lambert Jean-Marie JM Marchalot Anne A Martin Ophélie O Le Noir Sandrine S Pinaud Eric E Ayala Maria Victoria MV Sirac Christophe C Saulière Jérôme J Moreaux Jérôme J Cogné Michel M Delpy Laurent L

Cellular & molecular immunology 20180820 10

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 truncate ...[more]

PMID: 30127381

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Project description:BackgroundThe human genome contains a large number of gene clusters with multiple-variable-first exons, including the drug-metabolizing UDP glucuronosyltransferase (UGT1) and I-branching beta-1,6-N-acetylglucosaminyltransferase (GCNT2, also known as IGNT) clusters, organized in a tandem array, similar to that of the protocadherin (PCDH), immunoglobulin (IG), and T-cell receptor (TCR) clusters. To gain insight into the evolutionary processes that may have shaped their diversity, we performed comprehensive comparative analyses for vertebrate multiple-variable-first-exon clusters.ResultsWe found that there are species-specific variable-exon duplications and mutations in the vertebrate Ugt1, Gcnt2, and Ugt2a clusters and that their variable and constant genomic organizations are conserved and vertebrate-specific. In addition, analyzing the complete repertoires of closely-related Ugt2 clusters in humans, mice, and rats revealed extensive lineage-specific duplications. In contrast to the Pcdh gene clusters, gene conversion does not play a predominant role in the evolution of the vertebrate Ugt1, Gcnt2 and Ugt2 gene clusters. Thus, their tremendous diversity is achieved through "birth-and-death" evolution. Comparative analyses and homologous modeling demonstrated that vertebrate UGT proteins have similar three-dimensional structures each with N-terminal and C-terminal Rossmann-fold domains binding acceptor and donor substrates, respectively. Molecular docking experiments identified key residues in donor and acceptor recognition and provided insight into the catalytic mechanism of UGT glucuronidation, suggesting the human UGT1A1 residue histidine 39 (H39) as a general base and the residue aspartic acid 151 (D151) as an important electron-transfer helper. In addition, we identified four hypervariable regions in the N-terminal Rossmann domain that form an acceptor-binding pocket. Finally, analyzing patterns of nonsynonymous and synonymous nucleotide substitutions identified codon sites that are subject to positive Darwinian selection at the molecular level. These diversified residues likely play an important role in recognition of myriad xenobiotics and endobiotics.ConclusionOur results suggest that enormous diversity of vertebrate multiple variable first exons is achieved through birth-and-death evolution and that adaptive evolution of specific codon sites enhances vertebrate UGT diversity for defense against environmental agents. Our results also have interesting implications regarding the staggering molecular diversity required for chemical detoxification and drug clearance.

Dataset Information

Physiological and druggable skipping of immunoglobulin variable exons in plasma cells.

Publications

Physiological and druggable skipping of immunoglobulin variable exons in plasma cells.

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