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BZIP intron RNA motif

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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]

Consensus structure

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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

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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

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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

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  1. ^ a b c d e f 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. ^ a b c 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. ^ a b 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. ^ a b 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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