BZIP intron RNA motif

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Consensus structure of bZIP mRNA around the unconventional intron HAC mRNA.png
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 Ire1, a kinase with endoribonuclease activity. [1] 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 splicing was first described for HAC1 in S. cerevisiae . [1]

Contents

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 CNG'CNG 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. [2] In Saccharomyces cerevisiae the long intron pairs with the 5′ UTR and stalls the ribosomes on the mRNA. [3]

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 IRE1 proteins. [1] [4] IRE1 recognizes splice-site motifs in bZIP transcript and cleaves it. [1] [5] Stem-loop structures around the splice sites and IRE1-specific sequence motifs are both necessary and sufficient for splicing to occur. [1] The joining of exons is performed by tRNA ligase (TRL1 in Saccharomyces cerevisiae ). [6]

Intron conservation

Ire-mediated unconventional splicing of the bZIP intron has been confirmed experimentally in the following species:

Computational methods predict a bZIP intron with its characteristic RNA structure in 128 out of 156 species studied. [2] 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. [2]

References

  1. 1 2 3 4 5 6 Sidrauski C, Walter P (1997). "The transmembrane kinase Ire1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response". Cell. 90 (6): 1031–1039. doi: 10.1016/S0092-8674(00)80369-4 . PMID   9323131.
  2. 1 2 3 Hooks KB, Griffiths-Jones S (2011). "Conserved RNA structures in the non-canonical Hac1/Xbp1 intron". RNA Biol. 8 (4): 552–556. doi:10.4161/rna.8.4.15396. PMC   3225973 . PMID   21593604.
  3. ↑ Ruegsegger U, Leber JH, Walter P (2001). "Block of HAC1 mRNA translation by long-range base pairing is released by cytoplasmic splicing upon induction of the unfolded protein response". Cell. 107 (1): 103–114. doi: 10.1016/S0092-8674(01)00505-0 . PMID   11595189.
  4. 1 2 Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K (2001). "XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor". Cell. 107 (7): 881–891. doi: 10.1016/S0092-8674(01)00611-0 . PMID   11779464.
  5. 1 2 Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, Clark SG, Ron D (2002). "IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA". Nature. 415 (6867): 92–96. Bibcode:2002Natur.415...92C. doi:10.1038/415092a. PMID   11780124. S2CID   4319118.
  6. ↑ Sidrauski C, Cox JS, Walter P (1996). "tRNA ligase is required for regulated mRNA splicing in the unfolded protein response". Cell. 87 (3): 405–413. doi: 10.1016/S0092-8674(00)81361-6 . PMID   8898194.
  7. ↑ Wimalasena TT, Enjalbert B, Guillemette T, Plumridge A, Budge S, Yin Z, Brown AJ, Archer DB (2008). "Impact of the unfolded protein response upon genome-wide expression patterns, and the role of Hac1 in the polarized growth, of Candida albicans" (PDF). Fungal Genet Biol. 45 (9): 1235–1247. doi:10.1016/j.fgb.2008.06.001. PMID   18602013.
  8. ↑ Oh MH, Cheon SA, Kang HA, Kim JY (2010). "Functional characterization of the unconventional splicing of Yarrowia lipolytica HAC1 mRNA induced by unfolded protein response". Yeast. 27 (7): 443–452. doi:10.1002/yea.1762. PMID   20162530. S2CID   26839039.
  9. ↑ Guerfal M, Ryckaert S, Jacobs PP, Ameloot P, Van Craenenbroeck K, Derycke R, Callewaert N (2010). "The HAC1 gene from Pichia pastoris: characterization and effect of its overexpression on the production of secreted, surface displayed and membrane proteins". Microb Cell Fact. 9: 49. doi: 10.1186/1475-2859-9-49 . PMC   2905327 . PMID   20591165.
  10. ↑ Iracane, Elise; Donovan, Paul D.; Ola, Mihaela; Butler, Geraldine; Holland, Linda M. (2018). Mitchell, Aaron P. (ed.). "Identification of an Exceptionally Long Intron in the HAC1 Gene of Candida parapsilosis". mSphere. 3 (6). doi:10.1128/mSphere.00532-18. ISSN   2379-5042. PMC   6222058 . PMID   30404939.
  11. ↑ Ryoo HD, Domingos PM, Kang MJ, Steller H (2007). "Unfolded protein response in a Drosophila model for retinal degeneration". EMBO J. 26 (1): 242–252. doi:10.1038/sj.emboj.7601477. PMC   1782370 . PMID   17170705.
  12. ↑ Johnston, Brittany A.; Hooks, Katarzyna B.; McKinstry, Mia; Snow, Jonathan W. (2016). "Divergent forms of endoplasmic reticulum stress trigger a robust unfolded protein response in honey bees". Journal of Insect Physiology. 86: 1–10. doi:10.1016/j.jinsphys.2015.12.004. PMID   26699660.
  13. ↑ Li, Ting; Li, Hua; Peng, Shaoqing; Zhang, Fumiao; An, Liguo; Yang, Guiwen (2017). "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". Fish & Shellfish Immunology. 67: 667–674. doi:10.1016/j.fsi.2017.06.055. PMID   28663129. S2CID   29130644.
  14. ↑ Chen, Yi-Hong; Zhao, Li; Pang, Li-Ran; Li, Xiao-Yun; Weng, Shao-Ping; He, Jian-Guo (2012). "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". Developmental & Comparative Immunology. 38 (1): 66–77. doi:10.1016/j.dci.2012.04.005. PMID   22554476.
  15. ↑ Saloheimo M, Valkonen M, Penttila M (2003). "Activation mechanisms of the HAC1-mediated unfolded protein response in filamentous fungi". Mol Microbiol. 47 (4): 1149–1161. doi:10.1046/j.1365-2958.2003.03363.x. PMID   12581366. S2CID   24038414.
  16. ↑ Montenegro-Montero A, Goity A, Larrondo LF (2015). "The bZIP Transcription Factor HAC-1 Is Involved in the Unfolded Protein Response and Is Necessary for Growth on Cellulose in Neurospora crassa". PLOS ONE. 10 (7): e013141. Bibcode:2015PLoSO..1031415M. doi: 10.1371/journal.pone.0131415 . PMC   4488935 . PMID   26132395.
  17. ↑ Fan F, Ma G, Li J, Liu Q, Benz JP, Tian C, Ma Y (2015). "Genome-wide analysis of the endoplasmic reticulum stress response during lignocellulase production in Neurospora crassa". Biotechnol Biofuels. 8 (66): 66. doi: 10.1186/s13068-015-0248-5 . PMC   4399147 . PMID   25883682.
  18. ↑ Cheon, Seon Ah; Jung, Kwang-Woo; Chen, Ying-Lien; Heitman, Joseph; Bahn, Yong-Sun; Kang, Hyun Ah (2011). Doering, Tamara L. (ed.). "Unique Evolution of the UPR Pathway with a Novel bZIP Transcription Factor, Hxl1, for Controlling Pathogenicity of Cryptococcus neoformans". PLOS Pathogens. 7 (8) e1002177. doi: 10.1371/journal.ppat.1002177 . ISSN   1553-7374. PMC   3154848 . PMID   21852949.
  19. ↑ Heimel, Kai; Freitag, Johannes; Hampel, Martin; Ast, Julia; Bölker, Michael; Kämper, Jörg (2013). "Crosstalk between the Unfolded Protein Response and Pathways That Regulate Pathogenic Development in Ustilago maydis". The Plant Cell. 25 (10): 4262–4277. doi:10.1105/tpc.113.115899. ISSN   1040-4651. PMC   3877826 . PMID   24179126.
  20. ↑ Deng, Y.; Humbert, S.; Liu, J.-X.; Srivastava, R.; Rothstein, S. J.; Howell, S. H. (2011). "Heat induces the splicing by IRE1 of a mRNA encoding a transcription factor involved in the unfolded protein response in Arabidopsis". Proceedings of the National Academy of Sciences. 108 (17): 7247–7252. Bibcode:2011PNAS..108.7247D. doi: 10.1073/pnas.1102117108 . ISSN   0027-8424. PMC   3084119 . PMID   21482766.
  21. ↑ Nagashima, Yukihiro; Mishiba, Kei-ichiro; Suzuki, Eiji; Shimada, Yukihisa; Iwata, Yuji; Koizumi, Nozomu (2011). "Arabidopsis IRE1 catalyses unconventional splicing of bZIP60 mRNA to produce the active transcription factor". Scientific Reports. 1 (1): 29. Bibcode:2011NatSR...1E..29N. doi:10.1038/srep00029. ISSN   2045-2322. PMC   3216516 . PMID   22355548.
  22. ↑ Li, Yanjie; Humbert, Sabrina; Howell, Stephen H (2012). "ZmbZIP60 mRNA is spliced in maize in response to ER stress". BMC Research Notes. 5 (1): 144. doi: 10.1186/1756-0500-5-144 . ISSN   1756-0500. PMC   3369818 . PMID   22417282.
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