Unconventional splicing of<i>XBP1</i>mRNA occurs in the cytoplasm during the mammalian unfolded protein response

Uemura, Aya; Oku, Masaya; Mori, Kazutoshi; Yoshida, Hiderou

doi:10.1242/jcs.040584

Cited by 138 publications

(108 citation statements)

References 81 publications

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“…G 21 added to the 59 end of tRNA His is not shown. rRNA, and snRNAs (van Hoof et al 2000;Copela et al 2008;Ozanick et al 2009). RNase Z, Trz1, is the endonuclease that participates in 39 end processing for both mitochondrial and nuclear encoded tRNAs (Chen et al 2005;Daoud et al 2011;Maraia and Lamichhane 2011).…”

Section: Removal Of 59 Leader and 39 Trailer Sequences From Pre-trnasmentioning

confidence: 99%

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Transfer RNA Post-Transcriptional Processing, Turnover, and Subcellular Dynamics in the YeastSaccharomyces cerevisiae

2013

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Transfer RNAs (tRNAs) are essential for protein synthesis. In eukaryotes, tRNA biosynthesis employs a specialized RNA polymerase that generates initial transcripts that must be subsequently altered via a multitude of post-transcriptional steps before the tRNAs beome mature molecules that function in protein synthesis. Genetic, genomic, biochemical, and cell biological approaches possible in the powerful Saccharomyces cerevisiae system have led to exciting advances in our understandings of tRNA post-transcriptional processing as well as to novel insights into tRNA turnover and tRNA subcellular dynamics. tRNA processing steps include removal of transcribed leader and trailer sequences, addition of CCA to the 39 mature sequence and, for tRNA His , addition of a 59 G. About 20% of yeast tRNAs are encoded by intron-containing genes. The three-step splicing process to remove the introns surprisingly occurs in the cytoplasm in yeast and each of the splicing enzymes appears to moonlight in functions in addition to tRNA splicing. There are 25 different nucleoside modifications that are added post-transcriptionally, creating tRNAs in which 15% of the residues are nucleosides other than A, G, U, or C. These modified nucleosides serve numerous important functions including tRNA discrimination, translation fidelity, and tRNA quality control. Mature tRNAs are very stable, but nevertheless yeast cells possess multiple pathways to degrade inappropriately processed or folded tRNAs. Mature tRNAs are also dynamic in cells, moving from the cytoplasm to the nucleus and back again to the cytoplasm; the mechanism and function of this retrograde process is poorly understood. Here, the state of knowledge for tRNA post-transcriptional processing, turnover, and subcellular dynamics is addressed, highlighting the questions that remain. TABLE OF CONTENTS Abstract 43Introduction 44

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Section: Removal Of 59 Leader and 39 Trailer Sequences From Pre-trnasmentioning

confidence: 99%

“…As the HAC1 mRNA splicing reaction occurs on polyribosomes, Trl1 has the predicted cytoplasmic location. Splicing of the HAC1 mRNA vertebrate homolog XBP1 also occurs by the nonconventional protein catalyzed mechanism, but the ligase has not been defined (Uemura et al 2009). …”

Section: Removal Of 59 Leader and 39 Trailer Sequences From Pre-trnasmentioning

confidence: 99%

Transfer RNA Post-Transcriptional Processing, Turnover, and Subcellular Dynamics in the YeastSaccharomyces cerevisiae

2013

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“…IRE1 cleaves unspliced XBP1 mRNA (XBP1(U) mRNA), and an unidentified RNA ligase ligates its exons, resulting in the production of spliced XBP1 mRNA (XBP1(S) mRNA) (Calfon et al, 2002;Shen et al, 2001;Yoshida et al, 2001a). Because this splicing mechanism of XBP1 mRNA is independent of conventional mRNA splicing machinery, and its reaction occurs in the cytoplasm, it is called cytoplasmic splicing or frame switch splicing (Mori, 2003;Ruegsegger et al, 2001;Uemura et al, 2009). The splicing reaction removes a 26 nt-long intron from XBP1(U) mRNA, resulting in a frame shift in the XBP1(S) mRNA.…”

Section: Introductionmentioning

confidence: 99%

UBC9 Regulates the Stability of XBP1, a Key Transcription Factor Controlling the ER Stress Response

Uemura

Taniguchi

Matsuo

et al. 2013

Cell Struct. Funct.

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ABSTRACT. XBP1 is a key transcription factor regulating the mammalian endoplasmic reticulum (ER) stress response, which is a cytoprotective mechanism for dealing with an accumulation of unfolded proteins in the ER (ER stress). The expression of XBP1 is regulated by two different mechanisms: mRNA splicing and protein stability. When ER stress occurs, unspliced XBP1 mRNA is converted to mature mRNA, from which an active transcription factor, pXBP1(S), is translated and activates the transcription of ER-related genes to dispose of unfolded proteins. In the absence of ER stress, pXBP1(U) is translated from unspliced XBP1 mRNA and enhances the degradation of pXBP1(S). Here, we analyzed the regulatory mechanism of pXBP1(S) stability, and found that a SUMO-conjugase, UBC9, specifically bound to the leucine zipper motif of pXBP1(S) and increased the stability of pXBP1(S). Suppression of UBC9 expression by RNA interference reduced both the expression of pXBP1(S) and ER stress-induced transcription by pXBP1(S). Interestingly, overexpression of a UBC9 mutant deficient in SUMO-conjugating activity was able to increase pXBP1(S) expression as well as wild-type UBC9, indicating that UBC9 stabilizes pXBP1(S) without conjugating SUMO moieties. From these observations, we concluded that UBC9 is a novel regulator of the mammalian ER stress response.

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“…IRE1-mediated splicing is unconventional because mRNA splicing normally occurs in the nucleus, not in the cytoplasm (9). IRE1 is a type I membrane-spanning protein situated in the ER with its N terminus facing the ER lumen and its C terminus, which possesses catalytic functions, facing the cytosol.…”

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Heat induces the splicing by IRE1 of a mRNA encoding a transcription factor involved in the unfolded protein response in Arabidopsis

Deng

Humbert

Liu

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

409

487

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Adverse environmental conditions produce endoplasmic reticulum (ER) stress in plants. In response to heat or ER stress agents, Arabidopsis seedlings mitigate stress damage by activating ERassociated transcription factors and a RNA splicing factor, IRE1b. IRE1b splices the mRNA-encoding bZIP60, a basic leucine-zipper domain containing transcription factor associated with the unfolded protein response in plants. bZIP60 is required for the upregulation of BINDING PROTEIN3 (BIP3) in response to ER stress, and loss-of-function mutations in IRE1b or point mutations in the splicing site of bZIP60 mRNA are defective in BIP3 induction. These findings demonstrate that bZIP60 in plants is activated by RNA splicing and afford opportunities for monitoring and modulating stress responses in plants.abiotic stress | heat stress | RNA splicing | signal transduction H eat and drought tolerance are some of the most complex and important adaptive traits in plants. These stresses are foremost in placing limits on plant productivity worldwide, and tolerance to these stresses are among the most highly sought after traits in crops (1), particularly in the face of climate change.The unfolded protein response (UPR) in eukaryotes is an ER stress response that activates three different classes of membraneassociated sensor transducers in mammalian cells-activating transcription factor 6 (ATF6), inositol-requiring enzyme-1 (IRE1) and protein kinase RNA (PKR)-like ER kinase. Yeast has only one ER stress transducer, IRE1; nonetheless, this factor sets off a massive UPR by triggering the expression of >5% of genes in the yeast genome. Many of these encode chaperones and ER-associated protein degradation components (2). IRE1 in yeast and mammalian cells acts by splicing a messenger RNA encoding a transcription factor that, then in turn, activates the expression of stress response genes (see recent reviews; refs. 3-5). Yeast cells splice an mRNA encoding a transcription factor called Hac1p (6, 7). The unspliced form of the Hac1 messenger RNA attenuates its own translation, and splicing relieves the translational repression (8).IRE1-mediated splicing is unconventional because mRNA splicing normally occurs in the nucleus, not in the cytoplasm (9). IRE1 is a type I membrane-spanning protein situated in the ER with its N terminus facing the ER lumen and its C terminus, which possesses catalytic functions, facing the cytosol. IRE1 is regarded as a dual functional enzyme possessing both serine/threonine protein kinase and endoribonuclease activity (10). Upon activation, the IRE1 dimer undergoes autotransphosphorylation in which one monomer phosphorylates the other (11). Through the analysis of the structure of the cytosolic domain of IRE1, Lee et al. (12) found that dimerization brings together the kinase domains in a face-to-face manner that would seemingly facilitate autotransphosphorylation.Autotransphosphorylation is then thought to open a nucleotide-binding site that, when occupied, produces a conformational change in the cytosolic domain so as t...

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Unconventional splicing ofXBP1mRNA occurs in the cytoplasm during the mammalian unfolded protein response

Abstract: (2005

Cited by 138 publications

References 81 publications

Transfer RNA Post-Transcriptional Processing, Turnover, and Subcellular Dynamics in the YeastSaccharomyces cerevisiae

Transfer RNA Post-Transcriptional Processing, Turnover, and Subcellular Dynamics in the YeastSaccharomyces cerevisiae

UBC9 Regulates the Stability of XBP1, a Key Transcription Factor Controlling the ER Stress Response

Heat induces the splicing by IRE1 of a mRNA encoding a transcription factor involved in the unfolded protein response in Arabidopsis

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