Project description:The unfolded protein response (UPR) allows the endoplasmic reticulum (ER) to recover from the accumulation of misfolded proteins, in part by increasing its folding capacity. IRE1 promotes this remodeling by detecting misfolded ER proteins and activating a transcription factor, XBP-1, through endonucleolytic cleavage of its mRNA. We found that IRE1 independently mediated the rapid degradation of a specific subset of mRNAs. The arrays deposited here show the effects of depletion of IRE1 and XBP-1 on UPR induction in S2 cells. We have characterized the IRE1-dependent repressive branch of this response. Keywords: stress response, RNAi, DTT
Project description:Ire1 is an endoplasmic reticulum (ER)-located transmembrane protein that triggers the unfolded protein response. I recently noticed that Ire1 is activated not only in response to ER accumulation of unfolded proteins but also alongside diauxic shift in yeast Saccharomyces cerevisiae cells. I thus asked how different the Ire1-target genes upon two distinct scenes, a canonical ER -stressing stimuli and diauxic shift. Thus NGS transcriptome analysis was performed by using IRE1+ and ire1-delta mutant yeast cells under these conditions.
Project description:RNA ligation can regulate RNA function by altering RNA sequence, structure and coding potential. For example, the function of XBP1 in mediating the unfolded protein response requires RNA ligation, as does the maturation of some tRNAs. Here, we describe a novel in vivo model in C. elegans for the conserved RNA ligase RtcB, and show that RtcB ligates the xbp 1 mRNA during the IRE 1 branch of the unfolded protein response. Without RtcB, protein stress results in the accumulation of unligated xbp-1 mRNA fragments, defects in the unfolded protein response, and decreased lifespan. RtcB also ligates endogenous pre tRNA halves, and RtcB mutants have defects in growth and lifespan that can be bypassed by expression of pre-spliced tRNAs. In addition, animals that lack RtcB have defects that are independent of tRNA maturation and the unfolded protein response. Thus, RNA ligation by RtcB is required for the function of multiple endogenous target RNAs including both xbp-1 and tRNAs. RtcB is uniquely capable of performing these ligation functions, and RNA ligation by RtcB mediates multiple essential processes in vivo. 4 paired-end RNA-seq reads. Control worms have pre-spliced tRNAs, RtcB-null have mutated RtcB, +/- tunicamycin treatment
Project description:RNA ligation can regulate RNA function by altering RNA sequence, structure and coding potential. For example, the function of XBP1 in mediating the unfolded protein response requires RNA ligation, as does the maturation of some tRNAs. Here, we describe a novel in vivo model in C. elegans for the conserved RNA ligase RtcB, and show that RtcB ligates the xbp 1 mRNA during the IRE 1 branch of the unfolded protein response. Without RtcB, protein stress results in the accumulation of unligated xbp-1 mRNA fragments, defects in the unfolded protein response, and decreased lifespan. RtcB also ligates endogenous pre tRNA halves, and RtcB mutants have defects in growth and lifespan that can be bypassed by expression of pre-spliced tRNAs. In addition, animals that lack RtcB have defects that are independent of tRNA maturation and the unfolded protein response. Thus, RNA ligation by RtcB is required for the function of multiple endogenous target RNAs including both xbp-1 and tRNAs. RtcB is uniquely capable of performing these ligation functions, and RNA ligation by RtcB mediates multiple essential processes in vivo.
Project description:Multiple myeloma (MM) evolves from highly prevalent premalignant condition termed Monoclonal Gammopathy of Undetermined Significance (MGUS). We report an MGUS-MM phenotype arising in transgenic mice with Emu-directed expression of the unfolded protein/ER stress response and plasma cell development spliced isoform factor XBP-1s. Emu-XBP-1s elicited elevated serum Ig and IL-6 levels, skin alterations and with advancing age, a significant proportion of Emu-xbp-1s transgenic mice develop features diagnostic of human MM including bone lytic lesions. Transcriptional profiles of Emu-xbp-1s B lymphoid and MM cells show aberrant expression of genes known to be dysregulated in human MM including Cyclin D1, MAF, MAFB, and APRIL. This genetic model coupled with documented frequent XBP-1s overexpression in human MM serve to implicate chronic XBP-1s dysregulation in the development of this common and lethal malignancy. Keywords: XBP-1, MGUS, multiple myeloma, transgenic mouse