The mammalian tRNA ligase complex mediates splicing of XBP1 mRNA and controls antibody secretion in plasma cells

The unfolded protein response (UPR) is a conserved stress‐signaling pathway activated after accumulation of unfolded proteins within the endoplasmic reticulum (ER). Active UPR signaling leads to unconventional, enzymatic splicing of XBP1 mRNA enabling expression of the transcription factor XBP1s to...

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Veröffentlicht in:The EMBO journal 2014-12, Vol.33 (24), p.2922-2936
Hauptverfasser: Jurkin, Jennifer, Henkel, Theresa, Nielsen, Anne Færch, Minnich, Martina, Popow, Johannes, Kaufmann, Therese, Heindl, Katrin, Hoffmann, Thomas, Busslinger, Meinrad, Martinez, Javier
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Sprache:eng
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Zusammenfassung:The unfolded protein response (UPR) is a conserved stress‐signaling pathway activated after accumulation of unfolded proteins within the endoplasmic reticulum (ER). Active UPR signaling leads to unconventional, enzymatic splicing of XBP1 mRNA enabling expression of the transcription factor XBP1s to control ER homeostasis. While IRE1 has been identified as the endoribonuclease required for cleavage of this mRNA, the corresponding ligase in mammalian cells has remained elusive. Here, we report that RTCB, the catalytic subunit of the tRNA ligase complex, and its co‐factor archease mediate XBP1 mRNA splicing both in vitro and in vivo . Depletion of RTCB in plasma cells of Rtcb fl/fl Cd23 ‐Cre mice prevents XBP1s expression, which normally is strongly induced during plasma cell development. RTCB‐depleted plasma cells show reduced and disorganized ER structures as well as severe defects in antibody secretion. Targeting RTCB and/or archease thus represents a promising strategy for the treatment of a growing number of diseases associated with elevated expression of XBP1s. Synopsis The capacity of B cells to differentiate into plasma cells and secrete high amounts of antibodies upon activation relies on the efficient splicing of the XBP1 mRNA, catalyzed by the tRNA ligase complex and its co‐factor archease during the unfolded protein response. The tRNA ligase RTCB and its co‐factor archease co‐localize at the endoplasmic reticulum to catalyze unconventional XBP1 mRNA splicing during the unfolded protein response. The presence of archease is needed to sustain full activity of the tRNA ligase complex and support XBP1 mRNA ligation. Depletion of RTCB in a conditional B‐cell‐specific knockout mouse model ( Rtcb fl/fl Cd23 ‐Cre) prevents XBP1s expression, which in normal conditions is strongly induced during plasma cell development. Ex vivo stimulated RTCB‐depleted B cells show distorted ER structures and severe defects in antibody secretion. In vivo, RTCB‐deficient mice show significantly reduced levels of serum immunoglobulins after immunization. Graphical Abstract The capacity of B cells to differentiate into plasma cells and secrete antibodies upon activation relies on the efficient splicing of the XBP1 mRNA, catalyzed by the tRNA ligase complex and its co‐factor archease during the unfolded protein response.
ISSN:0261-4189
1460-2075
DOI:10.15252/embj.201490332