Gene Symbol: HAC1
Description: transcription factor HAC1
Alias: ERN4, IRE15, transcription factor HAC1
Species: Saccharomyces cerevisiae S288c

Top Publications

  1. Cox J, Walter P. A novel mechanism for regulating activity of a transcription factor that controls the unfolded protein response. Cell. 1996;87:391-404 pubmed
    ..We propose that the complex regulation of Hac1p expression serves to provide multiple levels at which the UPR can be controlled. ..
  2. Chang H, Jones E, Henry S. Role of the unfolded protein response pathway in regulation of INO1 and in the sec14 bypass mechanism in Saccharomyces cerevisiae. Genetics. 2002;162:29-43 pubmed
    ..Finally, synthetic lethality involving sec14 and UPR mutations suggests that the UPR plays an essential role in survival of sec14 cki1 strains. ..
  3. Brickner J, Walter P. Gene recruitment of the activated INO1 locus to the nuclear membrane. PLoS Biol. 2004;2:e342 pubmed
    ..Recruitment requires the transcriptional activator Hac1, which is produced upon induction of the UPR, and is constitutive in a strain lacking Opi1...
  4. Sugiyama M, Nikawa J. The Saccharomyces cerevisiae Isw2p-Itc1p complex represses INO1 expression and maintains cell morphology. J Bacteriol. 2001;183:4985-93 pubmed
    ..b>HAC1 encodes a transcription factor which has a basic leucine zipper domain...
  5. Mori T, Ogasawara C, Inada T, Englert M, Beier H, Takezawa M, et al. Dual functions of yeast tRNA ligase in the unfolded protein response: unconventional cytoplasmic splicing of HAC1 pre-mRNA is not sufficient to release translational attenuation. Mol Biol Cell. 2010;21:3722-34 pubmed publisher
    ..In the yeast UPR, the unconventional splicing of HAC1 mRNA is a key step...
  6. Mori K, Kawahara T, Yoshida H, Yanagi H, Yura T. Signalling from endoplasmic reticulum to nucleus: transcription factor with a basic-leucine zipper motif is required for the unfolded protein-response pathway. Genes Cells. 1996;1:803-17 pubmed
    ..We then cloned the ERN4 (presumably identical with HAC1) gene using yeast one-hybrid screening, in which the GAL4-ERN4 fusion gene constitutively activates the UPR pathway...
  7. Kaufman R. Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev. 1999;13:1211-33 pubmed
  8. Welihinda A, Tirasophon W, Kaufman R. The transcriptional co-activator ADA5 is required for HAC1 mRNA processing in vivo. J Biol Chem. 2000;275:3377-81 pubmed
    ..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)...
  9. Sato M, Sato K, Nakano A. Evidence for the intimate relationship between vesicle budding from the ER and the unfolded protein response. Biochem Biophys Res Commun. 2002;296:560-7 pubmed
    ..The constitutive activation of the UPR by overexpression of either IRE1 or active mutant HAC1, a transcription factor responsible for the UPR, suppresses sec12-4...

More Information


  1. Higashio H, Kohno K. A genetic link between the unfolded protein response and vesicle formation from the endoplasmic reticulum. Biochem Biophys Res Commun. 2002;296:568-74 pubmed
    ..Unexpectedly, one of them was identified as HAC1, a gene encoding the basic leucine-zipper type transcription factor Hac1p...
  2. Leber J, Bernales S, Walter P. IRE1-independent gain control of the unfolded protein response. PLoS Biol. 2004;2:E235 pubmed
    ..Here we show that a heretofore unrecognized pathway operates in yeast to regulate the transcription of HAC1. The resulting increase in Hac1p production, combined with the production or activation of a putative UPR ..
  3. Nikawa J, Murakami A, Esumi E, Hosaka K. Cloning and sequence of the SCS2 gene, which can suppress the defect of INO1 expression in an inositol auxotrophic mutant of Saccharomyces cerevisiae. J Biochem. 1995;118:39-45 pubmed
    Saccharomyces cerevisiae ire15 mutant has a defect in the expression of INO1, showing the inositol auxotrophic phenotype [Nikawa, J. (1994) Gene 149, 367-372]...
  4. Patil C, Li H, Walter P. Gcn4p and novel upstream activating sequences regulate targets of the unfolded protein response. PLoS Biol. 2004;2:E246 pubmed
    ..The discovery of a role for Gcn4p in the yeast UPR reveals an additional level of complexity and demonstrates a surprising conservation of the signaling circuit between yeast and metazoan cells. ..
  5. Friedlander R, Jarosch E, Urban J, Volkwein C, Sommer T. A regulatory link between ER-associated protein degradation and the unfolded-protein response. Nat Cell Biol. 2000;2:379-84 pubmed
    ..However, when stress is applied, the UPR is required to increase ERAD activity. We thus demonstrate, for the first time, a regulatory loop between ERAD and the UPR, which is essential for normal growth of yeast cells. ..
  6. Delaney J, Ahmed U, Chou A, Sim S, Carr D, Murakami C, et al. Stress profiling of longevity mutants identifies Afg3 as a mitochondrial determinant of cytoplasmic mRNA translation and aging. Aging Cell. 2013;12:156-66 pubmed publisher
    ..These data demonstrate an unexpected link between a mitochondrial protease, cytoplasmic mRNA translation, and aging. ..
  7. Chang H, Jesch S, Gaspar M, Henry S. Role of the unfolded protein response pathway in secretory stress and regulation of INO1 expression in Saccharomyces cerevisiae. Genetics. 2004;168:1899-913 pubmed
    ..Indeed, many of the Sec(-) mutants that had elevated UPR expression at semipermissive growth temperatures failed to achieve wild-type levels of INO1 expression under these same conditions. ..
  8. Lee K, Dey M, Neculai D, Cao C, Dever T, Sicheri F. Structure of the dual enzyme Ire1 reveals the basis for catalysis and regulation in nonconventional RNA splicing. Cell. 2008;132:89-100 pubmed publisher
    ..These findings provide a basis for understanding the mechanism of action of RNaseL and other pseudokinases, which represent 10% of the human kinome. ..
  9. Nikawa J, Akiyoshi M, Hirata S, Fukuda T. Saccharomyces cerevisiae IRE2/HAC1 is involved in IRE1-mediated KAR2 expression. Nucleic Acids Res. 1996;24:4222-6 pubmed
    ..Sequencing analysis revealed that IRE2 is identical to HAC1, which encodes a transcription factor having a basic-leucine zipper motif...
  10. Weindling E, Bar Nun S. Sir2 links the unfolded protein response and the heat shock response in a stress response network. Biochem Biophys Res Commun. 2015;457:473-8 pubmed publisher
    ..Saccharomyces cerevisiae, HSR is regulated by transcription factor Hsf1, and UPR Ire1 branch activates transcription factor Hac1. Here we demonstrate systemic regulation of proteostasis through a direct link between UPR and HSR...
  11. Anshu A, Mannan M, Chakraborty A, Chakrabarti S, Dey M. A novel role for protein kinase Kin2 in regulating HAC1 mRNA translocation, splicing, and translation. Mol Cell Biol. 2015;35:199-210 pubmed publisher
    ..UPR activation involves (i) aggregation of the ER-resident kinase/RNase Ire1 to form an Ire1 focus, (ii) targeting HAC1 pre-mRNA toward the Ire1 focus that cleaves out an inhibitory intron from the mRNA, and (iii) translation of Hac1 ..
  12. Schroder M, Clark R, Liu C, Kaufman R. The unfolded protein response represses differentiation through the RPD3-SIN3 histone deacetylase. EMBO J. 2004;23:2281-92 pubmed
    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...
  13. Nikawa J, Kimura M. A novel function of the human chaperonin CCT epsilon subunit in yeast. Biosci Biotechnol Biochem. 2012;76:199-201 pubmed
    A malfunction in the yeast HAC1 causes the unfolding-protein response in the endoplasmic reticulum, resulting in stress-sensitive and inositol auxotrophic phenotypes...
  14. Epstein S, Kirkpatrick C, Castillon G, Muñiz M, Riezman I, David F, et al. Activation of the unfolded protein response pathway causes ceramide accumulation in yeast and INS-1E insulinoma cells. J Lipid Res. 2012;53:412-20 pubmed publisher
    ..Dependence on UPR was demonstrated by showing the HAC1-dependence of the suppression. A similar induction of ceramides by UPR seems to take place in mammalian cells...
  15. Cui H, Liu X, McCormick M, Wasko B, Zhao W, He X, et al. PMT1 deficiency enhances basal UPR activity and extends replicative lifespan of Saccharomyces cerevisiae. Age (Dordr). 2015;37:9788 pubmed publisher
    ..Relative to wild-type and PMT1-OX strains, the pmt1Δ strain had enhanced HAC1 mRNA splicing and elevated expression levels of UPR target genes...
  16. Labunskyy V, Gerashchenko M, Delaney J, Kaya A, Kennedy B, Kaeberlein M, et al. Lifespan extension conferred by endoplasmic reticulum secretory pathway deficiency requires induction of the unfolded protein response. PLoS Genet. 2014;10:e1004019 pubmed publisher
    ..These findings demonstrate that the UPR is an important determinant of lifespan that governs ER stress and identify a signaling network that couples stress resistance to longevity...
  17. Heimel K, Freitag J, Hampel M, Ast J, B lker M, K mper J. Crosstalk between the unfolded protein response and pathways that regulate pathogenic development in Ustilago maydis. Plant Cell. 2013;25:4262-77 pubmed publisher
    ..Here, we characterize the homologs of the central UPR regulatory proteins Hac1 (for Homologous to ATF/CREB1) and Inositol Requiring Enzyme1 in the plant pathogenic fungus Ustilago maydis and ..
  18. Horn S, Hanna J, Hirsch C, Volkwein C, Schütz A, Heinemann U, et al. Usa1 functions as a scaffold of the HRD-ubiquitin ligase. Mol Cell. 2009;36:782-93 pubmed publisher
    ..Our data demonstrate that scaffold proteins are required to adapt ubiquitin ligase activities toward different classes of substrates. ..
  19. Sathe L, Bolinger C, Mannan M, Dever T, Dey M. Evidence That Base-pairing Interaction between Intron and mRNA Leader Sequences Inhibits Initiation of HAC1 mRNA Translation in Yeast. J Biol Chem. 2015;290:21821-32 pubmed publisher
    The Hac1 transcription factor in yeast up-regulates a collection of genes that control protein homeostasis...
  20. Tan S, Teo M, Lam Y, Dawes I, Perrone G. Cu, Zn superoxide dismutase and NADP(H) homeostasis are required for tolerance of endoplasmic reticulum stress in Saccharomyces cerevisiae. Mol Biol Cell. 2009;20:1493-508 pubmed publisher
    ..Prior adaptation of the hac1 mutant deficient in the unfolded protein response (UPR) to the superoxide-generating agent paraquat reduced cell ..
  21. Kliewe F, Engelhardt M, Aref R, Schüller H. Promoter recruitment of corepressors Sin3 and Cyc8 by activator proteins of the yeast Saccharomyces cerevisiae. Curr Genet. 2017;63:739-750 pubmed publisher
    ..Recruitment of corepressors by an activator is not a regulatory exception as we could show that activators Pho4 and Hac1 also contain domains being able to interact with Sin3 and Cyc8.
  22. Schuck S, Prinz W, Thorn K, Voss C, Walter P. Membrane expansion alleviates endoplasmic reticulum stress independently of the unfolded protein response. J Cell Biol. 2009;187:525-36 pubmed publisher
    ..Thus, increasing ER size through membrane synthesis is an integral yet distinct part of the cellular program to overcome ER stress. ..
  23. Pal B, Chan N, Helfenbaum L, Tan K, Tansey W, Gething M. SCFCdc4-mediated degradation of the Hac1p transcription factor regulates the unfolded protein response in Saccharomyces cerevisiae. Mol Biol Cell. 2007;18:426-40 pubmed
  24. Tanaka N, Meineke B, Shuman S. RtcB, a novel RNA ligase, can catalyze tRNA splicing and HAC1 mRNA splicing in vivo. J Biol Chem. 2011;286:30253-7 pubmed publisher
    ..Moreover, RtcB can replace Trl1 as the catalyst of HAC1 mRNA splicing during the unfolded protein response...
  25. Hsu J, Tang P, Wang I, Liu C, Chen W, Tsai P, et al. Unfolded protein response regulates yeast small GTPase Arl1p activation at late Golgi via phosphorylation of Arf GEF Syt1p. Proc Natl Acad Sci U S A. 2016;113:E1683-90 pubmed publisher
    ..Thus, these findings clarify how the UPR influences the roles of Syt1p, Arl1p, and Imh1p in Golgi transport. ..
  26. Mizuno T, Masuda Y, Irie K. The Saccharomyces cerevisiae AMPK, Snf1, Negatively Regulates the Hog1 MAPK Pathway in ER Stress Response. PLoS Genet. 2015;11:e1005491 pubmed publisher
    ..Thus, Snf1 plays pleiotropic roles in ER stress response by negatively regulating the Hog1 MAPK pathway and the UPR pathway. ..
  27. Uchimura S, Sugiyama M, Nikawa J. Effects of N-glycosylation and inositol on the ER stress response in yeast Saccharomyces cerevisiae. Biosci Biotechnol Biochem. 2005;69:1274-80 pubmed
    IRE1 and HAC1 are essential for the unfolded protein response in the endoplasmic reticulum (ER). IRE1- and HAC1-disruptants require high concentrations of inositol for its normal growth...
  28. Herzog B, Popova B, Jakobshagen A, Shahpasandzadeh H, Braus G. Mutual cross talk between the regulators Hac1 of the unfolded protein response and Gcn4 of the general amino acid control of Saccharomyces cerevisiae. Eukaryot Cell. 2013;12:1142-54 pubmed publisher
    b>Hac1 is the activator of the cellular response to the accumulation of unfolded proteins in the endoplasmic reticulum...
  29. De Souza E, Pimentel F, Machado C, Martins L, da Silva W, Montero Lomel M, et al. The unfolded protein response has a protective role in yeast models of classic galactosemia. Dis Model Mech. 2014;7:55-61 pubmed publisher
    ..These results indicate that endoplasmic reticulum stress is induced under galactosemic conditions and underscores the importance of the unfolded protein response pathway to cellular adaptation in these models of classic galactosemia...
  30. Cakir B. Bax induces activation of the unfolded protein response by inducing HAC1 mRNA splicing in Saccharomyces cerevisiae. Yeast. 2012;29:395-406 pubmed publisher
    ..Furthermore, this correlated with the splicing of HAC1 mRNA, a gene involved in UPR activation...
  31. Hamdan N, Kritsiligkou P, Grant C. ER stress causes widespread protein aggregation and prion formation. J Cell Biol. 2017;216:2295-2304 pubmed publisher
    ..The onset of ER stress is known to correlate with various disease processes, and our data indicate that widespread amorphous and amyloid protein aggregation is an unanticipated outcome of such stress. ..
  32. Davydenko S, Feng D, Jantti J, Keränen S. Characterization of GPI14/YJR013w mutation that induces the cell wall integrity signalling pathway and results in increased protein production in Saccharomyces cerevisiae. Yeast. 2005;22:993-1009 pubmed
    ..These results suggest that partial inactivation of Gpi14p causes defects in the cell wall structure and suggest that compromised GPI anchor synthesis results in enhanced protein production via the cell wall integrity signalling pathway. ..
  33. Tsvetanova N, Riordan D, Brown P. The yeast Rab GTPase Ypt1 modulates unfolded protein response dynamics by regulating the stability of HAC1 RNA. PLoS Genet. 2012;8:e1002862 pubmed publisher
    ..yeast UPR is subject to intricate post-transcriptional regulation, involving recruitment of the RNA encoding the Hac1 transcription factor to the ER and its unconventional splicing...
  34. Metzger M, Michaelis S. Analysis of quality control substrates in distinct cellular compartments reveals a unique role for Rpn4p in tolerating misfolded membrane proteins. Mol Biol Cell. 2009;20:1006-19 pubmed publisher
    ..Among these is RPN4, highlighting the importance of the Rpn4p-dependent response in tolerating UPR-M/C stress. Further analysis suggests the requirement for Rpn4p reflects severe impairment of the proteasome by UPR-M/C stress. ..
  35. Pineau L, Colas J, Dupont S, Beney L, Fleurat Lessard P, Berjeaud J, et al. Lipid-induced ER stress: synergistic effects of sterols and saturated fatty acids. Traffic. 2009;10:673-90 pubmed publisher
    ..The present data are discussed in the context of human diseases that involve lipid deregulation. ..
  36. Cronin S, Rao R, Hampton R. Cod1p/Spf1p is a P-type ATPase involved in ER function and Ca2+ homeostasis. J Cell Biol. 2002;157:1017-28 pubmed
    ..inhibitor tunicamycin, and synthetic lethality with deletion of the unfolded protein response regulator HAC1. Expression of the Drosophila melanogaster homologue of Cod1p complemented the cod1Delta mutant...
  37. Beaupere C, Wasko B, Lorusso J, Kennedy B, Kaeberlein M, Labunskyy V. CAN1 Arginine Permease Deficiency Extends Yeast Replicative Lifespan via Translational Activation of Stress Response Genes. Cell Rep. 2017;18:1884-1892 pubmed publisher
    ..This study extends our understanding of the importance of translational control in regulating stress resistance and longevity. ..
  38. Cohen T, Mallory M, Strich R, Yao T. Hos2p/Set3p deacetylase complex signals secretory stress through the Mpk1p cell integrity pathway. Eukaryot Cell. 2008;7:1191-9 pubmed publisher
  39. Kajiwara K, Muneoka T, Watanabe Y, Karashima T, Kitagaki H, Funato K. Perturbation of sphingolipid metabolism induces endoplasmic reticulum stress-mediated mitochondrial apoptosis in budding yeast. Mol Microbiol. 2012;86:1246-61 pubmed publisher
  40. Parikh B, Tortora A, Li X, Tumer N. Ricin inhibits activation of the unfolded protein response by preventing splicing of the HAC1 mRNA. J Biol Chem. 2008;283:6145-53 pubmed publisher
    ..RTA could not inhibit UPR when the spliced form of HAC1 mRNA was provided in trans, indicating that it had a direct effect on UPR upstream of HAC1-dependent ..
  41. Niwa M, Patil C, DeRisi J, Walter P. Genome-scale approaches for discovering novel nonconventional splicing substrates of the Ire1 nuclease. Genome Biol. 2005;6:R3 pubmed
    ..Endonucleolytic cleavage of the intron from the HAC1 mRNA (encoding a UPR-specific transcription factor) is the first step in a nonconventional mRNA splicing pathway; ..
  42. Hancock L, Behta R, Lopes J. Genomic analysis of the Opi- phenotype. Genetics. 2006;173:621-34 pubmed
    ..Regulation in response to inositol is also coordinated with the unfolded protein response (UPR). Consistent with this, several Opi(-) mutants were found to affect the UPR (yhi9, ede1, and vps74). ..
  43. Di Santo R, Aboulhouda S, Weinberg D. The fail-safe mechanism of post-transcriptional silencing of unspliced HAC1 mRNA. elife. 2016;5: pubmed publisher
    i>HAC1 encodes a transcription factor that is the central effector of the unfolded protein response (UPR) in budding yeast...