Roughly half of mature B cells have biallelic rearrangements of immunoglobulin-encoding loci in which one allele encodes a nonfunctional protein due to frameshift mutations. Aberrantly rearranged alleles encoding the immunoglobulin-κ light chain can nevertheless generate truncated proteins via alternative RNA splicing. In The Journal of Experimental Medicine, Srour et al. reveal a previously unknown checkpoint in plasma cells that eliminates biallelically rearranged cells expressing truncated κ-chains. Premature termination codons within the variable (Vκ) exon can promote exon skipping, with transcripts retaining only the leader and constant regions. While mature and germinal center B cells tolerate expression of the κ-chains lacking V domains that arise from skipping of the Vκ exon, plasma cells show heightened endoplasmic reticulum stress when such truncated proteins are expressed and undergo rapid apoptosis, despite their expression of a second, functional allele. This checkpoint probably operates to eliminate those plasma cells bearing frameshift mutations as a result of somatic hypermutation.
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Dempsey, L. Plasma cell checkpoint. Nat Immunol 17, 229 (2016). https://doi.org/10.1038/ni.3401
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DOI: https://doi.org/10.1038/ni.3401