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

• Jennifer Jurkin ^[1] ; Theresa Henkel ^[1] ; Anne Færch Nielsen ^[3] ; Martina Minnich ^[2] ; Johannes Popow ^[4] ; Therese Kaufmann ^[1] ; Katrin Heindl ^[5] ; Thomas Hoffmann ^[2] ; Meinrad Busslinger ^[2] ; Javier Martinez ^[1]
  1. [1] Institute of Molecular Biotechnology

     Institute of Molecular Biotechnology

     Innere Stadt, Austria

     
  2. [2] Research Institute of Molecular Pathology

     Research Institute of Molecular Pathology

     Innere Stadt, Austria

     
  3. [3] 2 European Molecular Biology Organization (EMBO) Heidelberg, Germany
  4. [4] 4 European Molecular Biology Laboratory (EMBL) Heidelberg, Germany
  5. [5] 5 Whitehead Institute for Biomedical Research Cambridge, MA, USA

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 33, Nº. 24, 2014, págs. 2922-2936
• Idioma: inglés
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• Resumen

  • 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 Rtcbfl/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.