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The mammalian tRNA ligase complex mediates splicing of XBP1 mRNA and controls antibody secretion in plasma cells
Author(s) -
Jurkin Jennifer,
Henkel Theresa,
Nielsen Anne Færch,
Minnich Martina,
Popow Johannes,
Kaufmann Therese,
Heindl Katrin,
Hoffmann Thomas,
Busslinger Meinrad,
Martinez Javier
Publication year - 2014
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201490332
Subject(s) - xbp1 , biology , unfolded protein response , endoplasmic reticulum , rna splicing , microbiology and biotechnology , ubiquitin ligase , messenger rna , endoribonuclease , rnase p , rna , ubiquitin , biochemistry , gene
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 XBP 1s 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 XBP 1s.