View source for BZIP intron RNA motif

[[File:HAC mRNA.png|thumb|Consensus structure of bZIP mRNA around the unconventional intron]]
The '''bZIP intron RNA motif''' is an RNA structure guiding splicing of a non-canonical [[intron]] from [[bZIP]]-containing genes called HAC1 in [[yeast]], [[XBP1]] in [[Metazoa]], Hxl1 or Cib1 in [[Basidiomycota]] and bZIP60 in [[plants]]. Splicing is performed independently of the [[spliceosome]] by [[ERN1|Ire1]], a [[kinase]] with endoribonuclease activity.<ref name="Sidrauski">{{cite journal |doi=10.1016/S0092-8674(00)80369-4 |vauthors=Sidrauski C, Walter P |title=The transmembrane kinase Ire1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response |journal=Cell |volume=90 |issue=6 |pages=1031–1039 |year=1997 |pmid=9323131 |doi-access=free }}</ref> Exons are joined by a tRNA ligase. Recognition of the [[intron]] splice sites is mediated by a base-paired [[secondary structure]] of the [[mRNA]] that forms at the exon/intron boundaries. Splicing of the bZIP intron is a key regulatory step in the [[unfolded protein response]] (UPR). The Ire-mediated unconventional [[Alternative splicing|splicing]] was first described for HAC1 in ''[[S. cerevisiae]]''.<ref name="Sidrauski" />
==Consensus structure==
The secondary structure of the bZIP intron is very well conserved, and consists of two hairpins (H2 and H3) around the splice sites, and an extended hairpin (H1) that brings the splice sites together (see figure). The sequence of the intron is well conserved only around the splice sites. Non-canonical splicing motifs '''C'''N'''G'C'''N'''G''' in the loop region of H2 and H3 hairpins are conserved.
The consensus intron is very short in Metazoa (20, 23 or 26 nt). However, yeast species have a long (>100 nt) intron in HAC1.<ref name="Hooks">{{cite journal |doi= 10.4161/rna.8.4.15396|vauthors=Hooks KB, Griffiths-Jones S |title=Conserved RNA structures in the non-canonical Hac1/Xbp1 intron |journal=RNA Biol |volume=8 |issue=4 |pages=552–556 |year=2011 |pmid=21593604 |pmc=3225973}}</ref> In ''[[Saccharomyces cerevisiae]]'' the long [[intron]] pairs with the [[5′ UTR]] and stalls the [[ribosomes]] on the mRNA.<ref>{{cite journal |doi=10.1016/S0092-8674(01)00505-0 |vauthors=Ruegsegger U, Leber JH, Walter P |title=Block of HAC1 mRNA translation by long-range base pairing is released by cytoplasmic splicing upon induction of the unfolded protein response |journal=Cell |volume=107 |issue=1 |pages=103–114 |year=2001 |pmid=11595189 |doi-access=free }}</ref>
==Mechanism of splicing==
Environmental stress can cause proteins to misfold and aggregate. To protect from these undesirable processes, a cell can activate the unfolded protein response (UPR) pathway. Splicing of the bZIP mRNA by Ire1 is one of the highly regulated ways of activating the UPR in response to presence of unfolded proteins in the [[endoplasmic reticulum]] (ER). [[ER stress]] activates the endoribonucleolytic activity of [[ERN1|IRE1]] proteins.<ref name="Sidrauski" /><ref name="Yoshida">{{cite journal |doi=10.1016/S0092-8674(01)00611-0  |vauthors=Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K |title=XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor |journal=Cell |volume=107 |issue=7 |pages=881–891 |year=2001 |pmid=11779464 |doi-access=free }}</ref> [[ERN1|IRE1]] recognizes splice-site motifs in bZIP transcript and cleaves it.<ref name="Sidrauski" /><ref name="Calfon">{{cite journal |doi=10.1038/415092a |vauthors=Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, Clark SG, Ron D |title=IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA |journal=Nature |volume=415 |issue=6867 |pages=92–96 |year=2002 |pmid=11780124 |bibcode=2002Natur.415...92C |s2cid=4319118 }}</ref> Stem-loop structures around the splice sites and [[ERN1|IRE1]]-specific sequence motifs are both necessary and sufficient for splicing to occur.<ref name="Sidrauski" /> The joining of exons is performed by tRNA ligase (TRL1 in ''[[Saccharomyces cerevisiae]]'').<ref>{{cite journal |doi=10.1016/S0092-8674(00)81361-6 |vauthors=Sidrauski C, Cox JS, Walter P |title=tRNA ligase is required for regulated mRNA splicing in the unfolded protein response |journal=Cell |volume=87 |issue=3 |pages=405–413 |year=1996 |pmid=8898194 |doi-access=free }}</ref>
==Intron conservation==
Ire-mediated unconventional splicing of the bZIP intron has been confirmed experimentally in the following species:
* Yeast: ''[[S. cerevisiae]]'',<ref name="Sidrauski" /> ''[[Candida albicans]]'',<ref>{{cite journal|vauthors=Wimalasena TT, Enjalbert B, Guillemette T, Plumridge A, Budge S, Yin Z, Brown AJ, Archer DB|year=2008|title=Impact of the unfolded protein response upon genome-wide expression patterns, and the role of Hac1 in the polarized growth, of Candida albicans|journal=Fungal Genet Biol|volume=45|issue=9|pages=1235–1247|doi=10.1016/j.fgb.2008.06.001|pmid=18602013|url=https://hal.archives-ouvertes.fr/hal-02146795/file/Wimalasena%20Archer%202008.pdf}}<!--https://hal.archives-ouvertes.fr/hal-02146795/file/Wimalasena%20Archer%202008.pdf--></ref> ''[[Yarrowia lipolytica]]'',<ref>{{cite journal|vauthors=Oh MH, Cheon SA, Kang HA, Kim JY|year=2010|title=Functional characterization of the unconventional splicing of Yarrowia lipolytica HAC1 mRNA induced by unfolded protein response|journal=Yeast|volume=27|issue=7|pages=443–452|doi=10.1002/yea.1762|pmid=20162530|s2cid=26839039}}</ref> ''[[Pichia pastoris]]'',<ref>{{cite journal|vauthors=Guerfal M, Ryckaert S, Jacobs PP, Ameloot P, Van Craenenbroeck K, Derycke R, Callewaert N|year=2010|title=The HAC1 gene from Pichia pastoris: characterization and effect of its overexpression on the production of secreted, surface displayed and membrane proteins|journal=Microb Cell Fact|volume=9|pages=49|doi=10.1186/1475-2859-9-49|pmc=2905327|pmid=20591165 |doi-access=free }}</ref> ''[[Candida parapsilosis]]''<ref>{{Cite journal|last1=Iracane|first1=Elise|last2=Donovan|first2=Paul D.|last3=Ola|first3=Mihaela|last4=Butler|first4=Geraldine|last5=Holland|first5=Linda M.|year=2018|editor-last=Mitchell|editor-first=Aaron P.|title=Identification of an Exceptionally Long Intron in the HAC1 Gene of Candida parapsilosis|journal=mSphere|language=en|volume=3|issue=6|doi=10.1128/mSphere.00532-18|pmid=30404939|pmc=6222058|issn=2379-5042}}</ref>
* Animals: [[human]],<ref name="Yoshida" /> [[mouse]] and ''[[Caenorhabditis elegans]]'',<ref name="Calfon" /> [[Drosophila melanogaster|fruit fly]],<ref>{{cite journal|vauthors=Ryoo HD, Domingos PM, Kang MJ, Steller H|year=2007|title=Unfolded protein response in a Drosophila model for retinal degeneration|journal=EMBO J|volume=26|issue=1|pages=242–252|doi=10.1038/sj.emboj.7601477|pmc=1782370|pmid=17170705}}</ref> [[Western honey bee|honey bee]],<ref>{{Cite journal|last1=Johnston|first1=Brittany A.|last2=Hooks|first2=Katarzyna B.|last3=McKinstry|first3=Mia|last4=Snow|first4=Jonathan W.|year=2016|title=Divergent forms of endoplasmic reticulum stress trigger a robust unfolded protein response in honey bees|journal=Journal of Insect Physiology|language=en|volume=86|pages=1–10|doi=10.1016/j.jinsphys.2015.12.004|pmid=26699660}}</ref> [[Common carp|carp]],<ref>{{Cite journal|last1=Li|first1=Ting|last2=Li|first2=Hua|last3=Peng|first3=Shaoqing|last4=Zhang|first4=Fumiao|last5=An|first5=Liguo|last6=Yang|first6=Guiwen|year=2017|title=Molecular characterization and expression pattern of X box-binding protein-1 (XBP1) in common carp ( Cyprinus carpio L.): Indications for a role of XBP1 in antibacterial and antiviral immunity|journal=Fish & Shellfish Immunology|language=en|volume=67|pages=667–674|doi=10.1016/j.fsi.2017.06.055|pmid=28663129|s2cid=29130644}}</ref> [[whiteleg shrimp]]<ref>{{Cite journal|last1=Chen|first1=Yi-Hong|last2=Zhao|first2=Li|last3=Pang|first3=Li-Ran|last4=Li|first4=Xiao-Yun|last5=Weng|first5=Shao-Ping|last6=He|first6=Jian-Guo|year=2012|title=Identification and characterization of Inositol-requiring enzyme-1 and X-box binding protein 1, two proteins involved in the unfolded protein response of Litopenaeus vannamei|journal=Developmental & Comparative Immunology|language=en|volume=38|issue=1|pages=66–77|doi=10.1016/j.dci.2012.04.005|pmid=22554476}}</ref>
*Other Fungi: ''[[Trichoderma reesei]]'' and ''[[Aspergillus nidulans]]'',<ref>{{cite journal |doi=10.1046/j.1365-2958.2003.03363.x |vauthors=Saloheimo M, Valkonen M, Penttila M |title=Activation mechanisms of the HAC1-mediated unfolded protein response in filamentous fungi |journal=Mol Microbiol |volume=47 |issue=4 |pages=1149–1161 |year=2003 |pmid=12581366 |s2cid=24038414 |doi-access= }}</ref> ''[[Neurospora crassa]]'',<ref>{{cite journal|vauthors=Montenegro-Montero A, Goity A, Larrondo LF|year=2015|title=The bZIP Transcription Factor HAC-1 Is Involved in the Unfolded Protein Response and Is Necessary for Growth on Cellulose in Neurospora crassa|journal=PLOS ONE|volume=10|issue=7|pages=e013141|doi=10.1371/journal.pone.0131415|pmc=4488935|pmid=26132395|bibcode=2015PLoSO..1031415M|doi-access=free}}</ref><ref>{{cite journal|vauthors=Fan F, Ma G, Li J, Liu Q, Benz JP, Tian C, Ma Y|year=2015|title=Genome-wide analysis of the endoplasmic reticulum stress response during lignocellulase production in Neurospora crassa|journal=Biotechnol Biofuels|volume=8|issue=66|pages=66|doi=10.1186/s13068-015-0248-5|pmc=4399147|pmid=25883682 |doi-access=free }}</ref> ''[[Cryptococcus neoformans]]'',<ref>{{Cite journal|last1=Cheon|first1=Seon Ah|last2=Jung|first2=Kwang-Woo|last3=Chen|first3=Ying-Lien|last4=Heitman|first4=Joseph|last5=Bahn|first5=Yong-Sun|last6=Kang|first6=Hyun Ah|year=2011|editor-last=Doering|editor-first=Tamara L.|title=Unique Evolution of the UPR Pathway with a Novel bZIP Transcription Factor, Hxl1, for Controlling Pathogenicity of Cryptococcus neoformans|journal=PLOS Pathogens|language=en|volume=7|issue=8|pages=e1002177|doi=10.1371/journal.ppat.1002177|pmid=21852949|issn=1553-7374|pmc=3154848 |doi-access=free }}</ref> ''[[Ustilago maydis]]''<ref>{{Cite journal|last1=Heimel|first1=Kai|last2=Freitag|first2=Johannes|last3=Hampel|first3=Martin|last4=Ast|first4=Julia|last5=Bölker|first5=Michael|last6=Kämper|first6=Jörg|year=2013|title=Crosstalk between the Unfolded Protein Response and Pathways That Regulate Pathogenic Development in Ustilago maydis|journal=The Plant Cell|language=en|volume=25|issue=10|pages=4262–4277|doi=10.1105/tpc.113.115899|pmid=24179126|issn=1040-4651|pmc=3877826}}</ref>
* Plants: [[Arabidopsis thaliana]],<ref>{{Cite journal|last1=Deng|first1=Y.|last2=Humbert|first2=S.|last3=Liu|first3=J.-X.|last4=Srivastava|first4=R.|last5=Rothstein|first5=S. J.|last6=Howell|first6=S. H.|year=2011|title=Heat induces the splicing by IRE1 of a mRNA encoding a transcription factor involved in the unfolded protein response in Arabidopsis|journal=Proceedings of the National Academy of Sciences|language=en|volume=108|issue=17|pages=7247–7252|doi=10.1073/pnas.1102117108|pmid=21482766|pmc=3084119|bibcode=2011PNAS..108.7247D|issn=0027-8424|doi-access=free}}</ref><ref>{{Cite journal|last1=Nagashima|first1=Yukihiro|last2=Mishiba|first2=Kei-ichiro|last3=Suzuki|first3=Eiji|last4=Shimada|first4=Yukihisa|last5=Iwata|first5=Yuji|last6=Koizumi|first6=Nozomu|year=2011|title=Arabidopsis IRE1 catalyses unconventional splicing of bZIP60 mRNA to produce the active transcription factor|journal=Scientific Reports|language=en|volume=1|issue=1|page=29|doi=10.1038/srep00029|pmid=22355548|issn=2045-2322|pmc=3216516|bibcode=2011NatSR...1E..29N}}</ref> [[maize]].<ref>{{Cite journal|last1=Li|first1=Yanjie|last2=Humbert|first2=Sabrina|last3=Howell|first3=Stephen H|year=2012|title=ZmbZIP60 mRNA is spliced in maize in response to ER stress|journal=BMC Research Notes|language=en|volume=5|issue=1|page=144|doi=10.1186/1756-0500-5-144|pmid=22417282|pmc=3369818|issn=1756-0500|doi-access=free}}</ref>
Computational methods predict a bZIP [[intron]] with its characteristic [[RNA structure]] in 128 out of 156 species studied.<ref name="Hooks" /> In [[Fungi]] a bZIP intron was initially found only in [[Ascomycota]] (in 52 out of 63 species analysed) but experimental studies showed it is also present in [[Basidiomycota]] and other Candida species. All 45 [[vertebrate]] genomes analysed, 19 of [[Arthropoda]], 7 of [[Nematoda]], 2 of [[Annelida]] and 2 of [[Mollusca]] contain a characteristic HAC1-like structure in an [[open reading frame]].<ref name="Hooks" />
==References==
{{reflist|2}}
[[Category:RNA splicing]]
[[Category:Non-coding RNA]]