The Yin and Yang of RNA surveillance in B lymphocytes and antibody-secreting plasma cells

Abstract

The random V(D)J recombination process ensures the diversity of the primary immunoglobulin (Ig) repertoire. In two thirds of cases, imprecise recombination between variable (V), diversity (D), and joining (J) segments induces a frameshift in the open reading frame that leads to the appearance of premature termination codons (PTCs). Thus, many B lineage cells harbour biallelic V(D)J-rearrangements of Ig heavy or light chain genes, with a productively-recombined allele encoding the functional Ig chain and a nonproductive allele potentially encoding truncated Ig polypeptides. Since the pattern of Ig gene expression is mostly biallelic, transcription initiated from nonproductive Ig alleles generates considerable amounts of primary transcripts with out-of-frame V(D)J junctions. How RNA surveillance pathways cooperate to control the noise from nonproductive Ig genes will be discussed in this review, focusing on the benefits of nonsense-mediated mRNA decay (NMD) activation during B-cell development and detrimental effects of nonsense-associated altered splicing (NAS) in terminally differentiated plasma cells.

Nonsense-associated alternative splicing as a putative reno-protective mechanism in Pkhd1cyli/Pkhd1cyli mutant mice

“…Kidney Pkhd1 transcript profiles differed both qualitatively and quantitatively between normal and cyli/cyli mutant mice. Taken together, our observations suggest that the cyli mutation results in the activation of both nonsense-associated alternative splicing (NAS) [20-22] and nonsense-mediated decay (NMD) [22-27] mechanisms in mutant kidneys. We propose that in the cyli/cyli mouse, the absence of renal cystic disease is due to a combination of nonsense-associated alternative splicing (NAS) [20-22] that generates Pkhd1 mRNAs lacking mutated exon 48, thereby avoiding premature protein termination, and NMD eliminating the majority of normally-spliced exon 48-containing transcripts.…”

Mechanisms and Regulation of Nonsense-Mediated mRNA Decay and Nonsense-Associated Altered Splicing in Lymphocytes

“…In conclusion, NMD is a complex cellular process involving different pathways to ensure the efficient degradation of mRNAs harboring PTCs and to regulate the levels of physiological transcripts essential for cellular homeostasis. [82,83]. NP Ig heavy chain (IgH) mRNAs represent good EJC-dependent NMD substrates because PTCs are located within the VDJ exon or in the first constant exon (CH1).…”

“…By contrast, PTC-containing IgL mRNAs do not conform to the −50 nt boundary rule and harbor PTCs close to or within the last constant exon. Therefore, many B-lineage cells express PTC-containing Ig mRNAs that can activate both EJC-dependent and -independent NMD modes [82].…”

“…IgL transcripts are good models to study the magnitude of EJC-independent NMD because nonproductive VJ junctions cause the appearance of PTCs that do not fulfill the −50 nt boundary rule [82,95]. The downregulation of PTC-containing IgL mRNAs has been assessed during B-cell development using a mouse model that freely accumulates random IgL rearrangements in B cells without any selection for a functional BCR [94].…”

“…Consequences of NAS on Igκ transcripts in antibody-secreting plasma cells. Because most B-lineage cells harbor nonproductive (NP) Ig gene rearrangements[82,83], the boost of Ig gene transcription accompanying their plasma cell (PC) differentiation generates considerable amounts of nonsense Ig transcripts. In PCs with biallelic (VJ+/VJ−) Igκ rearrangements, the presence of premature termination codons (PTCs) activates NAS with skipping of the variable (V) exon.…”