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Gene Review

HAC1  -  Hac1p

Saccharomyces cerevisiae S288c

Synonyms: ERN4, IRE15, IRE2, Transcriptional activator HAC1, YFL031W
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Disease relevance of HAC1

  • Deletion of COD1 also impaired ER function, causing constitutive activation of the unfolded protein response, hypersensitivity to the glycosylation inhibitor tunicamycin, and synthetic lethality with deletion of the unfolded protein response regulator HAC1 [1].
  • Here, we show that the bacteriophage T4 enzymes RNA ligase 1 and polynucleotide kinase/phosphatase can fulfill the tRNA and HAC1 mRNA splicing functions of yeast Trl1 in vivo and bypass the requirement for Tpt1 [2].

High impact information on HAC1

  • We show that the polysomal, cytoplasmic pool of HAC1 mRNA is a substrate for splicing, suggesting that the stalled ribosomes may resume translation after the intron is removed [3].
  • Block of HAC1 mRNA translation by long-range base pairing is released by cytoplasmic splicing upon induction of the unfolded protein response [3].
  • Unspliced HAC1 mRNA is stable, located in the cytosol, and is associated with polyribosomes, yet does not produce protein, indicating that the ribosomes engaged on the mRNA are stalled [3].
  • In mammals, no Hac1p counterpart has yet been discovered despite the presence of Ire1p homologs in the endoplasmic reticulum [4].
  • The addition of purified tRNA ligase completes splicing; we therefore have reconstituted HAC1 mRNA splicing in vitro from purified components [5].

Biological context of HAC1

  • We characterized hac1Delta mutants in the sporulation-proficient SK1 genetic background and found a novel function for HAC1 in haploid tolerance. hac1Delta spore clones contain a diploid DNA content as determined by fluorescence-activated cell sorting and genetic analyses [6].
  • Here, we demonstrate that in addition to this well-understood ER stress signalling pathway, a second, IRE1, HAC1 and UPRE-independent mechanism for transcriptional activation upon ER stress, exists in yeast [7].
  • Ire1p regulates synthesis of the basic leucine-zipper (bZIP)-containing transcription factor Hac1p by controlling splicing of HAC1 mRNA [7].
  • We have characterized a yeast gene, IRE2, which was isolated as a suppressor gene that complements the inositol auxotrophic phenotype of the ire1 mutation [8].
  • The mechanisms by which mammalian IRE1 activates gene expression have not been completely characterized and mammalian HAC1 homologues have not been identified [9].

Anatomical context of HAC1

  • In Saccharomyces cerevisiae, splicing of HAC1 mRNA is initiated in response to the accumulation of unfolded proteins in the endoplasmic reticulum by the transmembrane kinase-endoribonuclease Ire1p [10].
  • To address this, we expressed yeast HAC1 in HeLa and HEK 293T human cell lines, both on its own and as fusions with yellow fluorescent protein (YFP) to investigate its processing and translation [11].
  • Recently, two mammalian homologues of Ire1p, IRE1 and IRE2, were identified. hIre1p, is preferentially localized to the nuclear envelope and requires a functional nuclease activity to transmit the UPR [12].
  • Our results suggest that the regulated splicing of HAC1 mRNA occurs by a novel pathway, involving tRNA ligase and bypassing the spliceosome [13].
  • While spliced HAC1 transcripts mobilized into polysomes, the vast majority of unspliced HAC1 RNA accumulated in nonpolysomal fractions before and after the carbon source shift, indicating that translation of unspliced HAC1 RNA is blocked at the translation initiation step, in addition to the previously reported elongation step [14].

Associations of HAC1 with chemical compounds

  • HAC1 encodes a transcription factor which has a basic leucine zipper domain [15].
  • However, we found an increase in the expression of KAR2 (karyogamy 2) gene, a well-known marker of ER (endoplasmic reticulum) stress and also observed HAC1 cleavage in homocysteine- and cysteinetreated cells, which indicates that homocysteine- and cysteine-mediated growth defect may probably be attributed to ER stress [16].
  • However, the luminal domain has extensively diverged from the yeast gene product. hIre1p expressed in mammalian cells displayed intrinsic autophosphorylation activity and an endoribonuclease activity that cleaved the 5' splice site of yeast HAC1 mRNA, a substrate for the endoribonuclease activity of yeast Ire1p [17].
  • Depletion of calcium ions (Ca2+) from the endoplasmic reticulum (ER) of yeast cells resulted in the activation of the unfolded protein response (UPR) signaling pathway involving Ire1p and Hac1p [18].
  • However, the hac1 disruptant becomes caffeine sensitive, which is suppressed by multicopy expression of the yeast PDE2 (Phosphodiesterase 2) gene [19].

Enzymatic interactions of HAC1

  • These results demonstrate that Ptc2p downregulates the UPR by dephosphorylating Ire1p and reveal a novel mechanism of regulation in the UPR pathway upstream of the HAC1 mRNA splicing event [20].
  • Trl1 also catalyzes splicing of HAC1 mRNA during the unfolded protein response [2].

Regulatory relationships of HAC1

  • Although the truncated form of ITC1 clearly suppressed the Ino(-) phenotype of the Delta hac1 strain, the full-length ITC1 had a moderate effect [15].
  • In the unfolded protein response induced by the reductant dithiothreitol, transcription factor Hac1 activates ERO1 transcription through a sequence that diverges from the consensus Hac1-binding sequence [21].
  • COS8 was then regulated by Hac1p, a bZip protein known to be involved in the unfolded protein response of S. cerevisiae, indicating, for the first time, a possible functional category for the Cos proteins of S. cerevisiae [22].
  • In the yeast UPR signaling pathway, the ER-located transmembrane protein Ire1 promotes splicing of the HAC1 premRNA (HAC1(u)) to produce the translatable transcription factor mRNA (HAC1i) [23].

Other interactions of HAC1

  • Strains carrying null alleles of PTC2 have a three- to fourfold-increased UPR and increased levels of spliced HAC1 mRNA [20].
  • The deletion analysis showed that only DNA fragments with the CDC43 and HAC1 genes can partially complement the rec41-1 mutation [24].
  • Activation of Ire1p kinase induces its endoribonuclease activity to cleave unspliced HAC1 mRNA and generate exon fragments that are subsequently ligated by tRNA ligase (RLG1) [25].
  • The transcriptional co-activator ADA5 is required for HAC1 mRNA processing in vivo [25].
  • Overexpression of both S. cerevisiae HAC1 and T. reesei hac1 caused an increase in the expression of the known UPR target gene KAR2 at early time points during cultivation [26].

Analytical, diagnostic and therapeutic context of HAC1

  • Our finding that one-sixth of spliced HAC1 mRNAs in yeast cells containing the T4 RNA-repair system suffered deletion of a single nucleotide at the 3' end of the splice-donor site suggests a model whereby the yeast RNA-repair system evolved a requirement for the 2'-PO(4) for RNA ligation to suppress inappropriate RNA recombination [2].


  1. Cod1p/Spf1p is a P-type ATPase involved in ER function and Ca2+ homeostasis. Cronin, S.R., Rao, R., Hampton, R.Y. J. Cell Biol. (2002) [Pubmed]
  2. Portability and fidelity of RNA-repair systems. Schwer, B., Sawaya, R., Ho, C.K., Shuman, S. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  3. Block of HAC1 mRNA translation by long-range base pairing is released by cytoplasmic splicing upon induction of the unfolded protein response. Rüegsegger, U., Leber, J.H., Walter, P. Cell (2001) [Pubmed]
  4. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Yoshida, H., Matsui, T., Yamamoto, A., Okada, T., Mori, K. Cell (2001) [Pubmed]
  5. The transmembrane kinase Ire1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response. Sidrauski, C., Walter, P. Cell (1997) [Pubmed]
  6. The unfolded protein response is required for haploid tolerance in yeast. Lee, K., Neigeborn, L., Kaufman, R.J. J. Biol. Chem. (2003) [Pubmed]
  7. IRE1- and HAC1-independent transcriptional regulation in the unfolded protein response of yeast. Schröder, M., Clark, R., Kaufman, R.J. Mol. Microbiol. (2003) [Pubmed]
  8. Saccharomyces cerevisiae IRE2/HAC1 is involved in IRE1-mediated KAR2 expression. Nikawa, J., Akiyoshi, M., Hirata, S., Fukuda, T. Nucleic Acids Res. (1996) [Pubmed]
  9. IRE1 and efferent signaling from the endoplasmic reticulum. Urano, F., Bertolotti, A., Ron, D. J. Cell. Sci. (2000) [Pubmed]
  10. The unfolded protein response represses differentiation through the RPD3-SIN3 histone deacetylase. Schröder, M., Clark, R., Liu, C.Y., Kaufman, R.J. EMBO J. (2004) [Pubmed]
  11. Differences in HAC1 mRNA processing and translation between yeast and mammalian cells indicate divergence of the eukaryotic ER stress response. Bowring, C.E., Llewellyn, D.H. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  12. The cellular response to protein misfolding in the endoplasmic reticulum. Welihinda, A.A., Tirasophon, W., Kaufman, R.J. Gene Expr. (1999) [Pubmed]
  13. tRNA ligase is required for regulated mRNA splicing in the unfolded protein response. Sidrauski, C., Cox, J.S., Walter, P. Cell (1996) [Pubmed]
  14. Global and specific translational regulation in the genomic response of Saccharomyces cerevisiae to a rapid transfer from a fermentable to a nonfermentable carbon source. Kuhn, K.M., DeRisi, J.L., Brown, P.O., Sarnow, P. Mol. Cell. Biol. (2001) [Pubmed]
  15. The Saccharomyces cerevisiae Isw2p-Itc1p complex represses INO1 expression and maintains cell morphology. Sugiyama, M., Nikawa, J. J. Bacteriol. (2001) [Pubmed]
  16. Homocysteine- and cysteine-mediated growth defect is not associated with induction of oxidative stress response genes in yeast. Kumar, A., John, L., Alam, M.M., Gupta, A., Sharma, G., Pillai, B., Sengupta, S. Biochem. J. (2006) [Pubmed]
  17. A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Tirasophon, W., Welihinda, A.A., Kaufman, R.J. Genes Dev. (1998) [Pubmed]
  18. Essential role of calcineurin in response to endoplasmic reticulum stress. Bonilla, M., Nastase, K.K., Cunningham, K.W. EMBO J. (2002) [Pubmed]
  19. Hac1: a novel yeast bZIP protein binding to the CRE motif is a multicopy suppressor for cdc10 mutant of Schizosaccharomyces pombe. Nojima, H., Leem, S.H., Araki, H., Sakai, A., Nakashima, N., Kanaoka, Y., Ono, Y. Nucleic Acids Res. (1994) [Pubmed]
  20. Protein serine/threonine phosphatase Ptc2p negatively regulates the unfolded-protein response by dephosphorylating Ire1p kinase. Welihinda, A.A., Tirasophon, W., Green, S.R., Kaufman, R.J. Mol. Cell. Biol. (1998) [Pubmed]
  21. Stress-induced transcription of the endoplasmic reticulum oxidoreductin gene ERO1 in the yeast Saccharomyces cerevisiae. Takemori, Y., Sakaguchi, A., Matsuda, S., Mizukami, Y., Sakurai, H. Mol. Genet. Genomics (2006) [Pubmed]
  22. ATF/CREB sites present in sub-telomeric regions of Saccharomyces cerevisiae chromosomes are part of promoters and act as UAS/URS of highly conserved COS genes. Spode, I., Maiwald, D., Hollenberg, C.P., Suckow, M. J. Mol. Biol. (2002) [Pubmed]
  23. Yeast unfolded protein response pathway regulates expression of genes for anti-oxidative stress and for cell surface proteins. Kimata, Y., Ishiwata-Kimata, Y., Yamada, S., Kohno, K. Genes Cells (2006) [Pubmed]
  24. The REC41 gene of Saccharomyces cerevisiae: isolation and genetic analysis. Chepurnaya, O.V., Kozhina, T.N., Peshekhonov, V.T., Korolev, V.G. Mutat. Res. (2001) [Pubmed]
  25. The transcriptional co-activator ADA5 is required for HAC1 mRNA processing in vivo. Welihinda, A.A., Tirasophon, W., Kaufman, R.J. J. Biol. Chem. (2000) [Pubmed]
  26. Effects of inactivation and constitutive expression of the unfolded- protein response pathway on protein production in the yeast Saccharomyces cerevisiae. Valkonen, M., Penttilä, M., Saloheimo, M. Appl. Environ. Microbiol. (2003) [Pubmed]
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