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.
['Jurkin|Jennifer|J|', 'Henkel|Theresa|T|', 'Nielsen|Anne Færch|AF|', 'Minnich|Martina|M|', 'Popow|Johannes|J|', 'Kaufmann|Therese|T|', 'Heindl|Katrin|K|', 'Hoffmann|Thomas|T|', 'Busslinger|Meinrad|M|', 'Martinez|Javier|J|']
D000604:Amino Acyl-tRNA Synthetases D000818:Animals D000906:Antibodies D004268:DNA-Binding Proteins D006367:HeLa Cells D006801:Humans D051379:Mice D010950:Plasma Cells D011506:Proteins D012326:RNA Splicing D012333:RNA, Messenger D016601:RNA-Binding Proteins D000071701:Regulatory Factor X Transcription Factors D014157:Transcription Factors D000071717:X-Box Binding Protein 1
antibody secretion plasma cells RTCB archease XBP1 mRNA splicing