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 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.
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.
Jennifer
J
Jurkin
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.
Theresa
T
Henkel
European Molecular Biology Organization (EMBO), Heidelberg, Germany.
Anne Færch
AF
Nielsen
Institute of Molecular Pathology (IMP), Vienna, Austria.
Martina
M
Minnich
European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
Johannes
J
Popow
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.
Therese
T
Kaufmann
Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
Katrin
K
Heindl
Institute of Molecular Pathology (IMP), Vienna, Austria.
Thomas
T
Hoffmann
Institute of Molecular Pathology (IMP), Vienna, Austria.
Meinrad
M
Busslinger
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria javier.martinez@imba.oeaw.ac.at.
Javier
J
Martinez
D000604:Amino Acyl-tRNA Synthetases / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D010950:Plasma Cells / Q000502:physiology*; D011506:Proteins / Q000378:metabolism*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000071717:X-Box Binding Protein 1
D000906:Antibodies; D004268:DNA-Binding Proteins; D011506:Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C000590560:ZBTB8OS protein, human; D000604:Amino Acyl-tRNA Synthetases; C556158:FAAP protein, mouse
RTCB; XBP1 mRNA splicing; antibody secretion; archease; plasma cells