Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Eukaryotic cells control the levels of molecular chaperones and folding enzymes in the endoplasmic reticulum (ER) by a transcriptional induction process termed the unfolded protein response (UPR) according to the needs within the ER. In Saccharomyces cerevisiae, expression of the UPR-specific transcription factor Hac1p is tightly regulated at the level of mRNA splicing that depends on an unconventional system. Thus, HAC1 precursor mRNA is constitutively expressed but not translated. A sensor molecule Ire1p/Ern1p-mediated signaling from the ER specifically removes an intron of 252 nucleotides from the precursor mRNA, and the resulting mature mRNA is translated to produce Hac1p. Because the 5' splice site is located near the C-terminal end of the Hac1p-coding region, this splicing replaces the last 10 codons of the ORF with an exon encoding 18 aa without affecting the N-terminal 220-aa region which contains the DNA-binding domain. Here, we found that this C-terminal 18-aa segment functions as a potent activation domain. Therefore, the splicing event joins the HAC1 DNA-binding domain to its activation domain, allowing rapid posttranscriptional generation of a potent transcriptional activator (238-aa Hac1p) that activates the UPR efficiently. This suggests that the UPR is hardly activated by Hac1p produced without splicing (230-aa Hac1p) which may occur in the absence of Ire1p/Ern1p-mediated signaling from the ER. Based on these and other results, we propose that the control of expression and activity of Hac1p meets the requirements of the ER.
 ...
PMID:mRNA splicing-mediated C-terminal replacement of transcription factor Hac1p is required for efficient activation of the unfolded protein response. 1078 Oct 71

All eukaryotic cells respond to the accumulation of unfolded proteins in the endoplasmic reticulum (ER) by signaling an adaptive pathway termed the unfolded protein response (UPR). In yeast, a type-I ER transmembrane protein kinase, Ire1p, is the proximal sensor of unfolded proteins in the ER lumen that initiates an unconventional splicing reaction on HAC1 mRNA. Hac1p is a transcription factor required for induction of UPR genes. In higher eukaryotic cells, the UPR also induces site-2 protease (S2P)-mediated cleavage of ER-localized ATF6 to generate an N-terminal fragment that activates transcription of UPR genes. To elucidate the requirements for IRE1alpha and ATF6 for signaling the mammalian UPR, we identified a UPR reporter gene that was defective for induction in IRE1alpha-null mouse embryonic fibroblasts and S2P-deficient Chinese hamster ovary (CHO) cells. We show that the endoribonuclease activity of IRE1alpha is required to splice XBP1 (X-box binding protein) mRNA to generate a new C terminus, thereby converting it into a potent UPR transcriptional activator. IRE1alpha was not required for ATF6 cleavage, nuclear translocation, or transcriptional activation. However, ATF6 cleavage was required for IRE1alpha-dependent induction of UPR transcription. We propose that nuclear-localized IRE1alpha and cytoplasmic-localized ATF6 signaling pathways merge through regulation of XBP1 activity to induce downstream gene expression. Whereas ATF6 increases the amount of XBP1 mRNA, IRE1alpha removes an unconventional 26-nucleotide intron that increases XBP1 transactivation potential. Both processing of ATF6 and IRE1alpha-mediated splicing of XBP1 mRNA are required for full activation of the UPR.
 ...
PMID:IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. 1185 Apr 8

Activation of the unfolded protein response (UPR) in eukaryotes involves the splicing of an unconventional intron from the mRNA encoding the transcriptional activator of the pathway. In Saccharomyces cerevisiae a 252-nucleotide (nt) unconventional intron is spliced out of the transcript of HAC1, changing the 3' end of the HAC1 open reading frame and relieving the transcript from a translational block in a single step. The translational block is caused by the base pairing of part of the unconventional intron with the 5'-untranslated region (5'UTR). In Aspergillus niger and other aspergilli, the unconventional intron in hacA mRNA is only 20 nt long. Since this intron is part of a stable stem-loop structure, base pairing with the 5'UTR, in contrast to the case with yeast HAC1, is not possible. However, analysis of the hacA mRNA revealed a GC-rich inverted repeat (18 base pairings). Upon the activation of the UPR, the 5'UTR of hacA mRNA is truncated by 230 nt, removing the left part of this inverted repeat. This implies a similar release of a translational block as in the case of S. cerevisiae HAC1 but in two steps. The mechanism behind the 5' truncation, which does not take place in either yeast HAC1 or mammalian xbp1 mRNA, has been hitherto unknown. Here we show that during secretion stress in A. niger, hacA transcription starts from a new start site closer to the ATG, relieving the transcript from translational attenuation. This transcriptional switch is mediated by HacA itself and the unfolded protein response element 2 (UPRE2) in the hacA promoter.
 ...
PMID:HacA-dependent transcriptional switch releases hacA mRNA from a translational block upon endoplasmic reticulum stress. 1918 70

Unfolded protein response (UPR) is an intracellular signaling pathway for adaptation to endoplasmic reticulum (ER) stress. In yeast UPR, Ire1 cleaves the unconventional intron of HAC1 mRNA, and the functional Hac1 protein translated from the spliced HAC1 mRNA induces the expression of ER chaperone genes and ER-associated degradation genes for the refolding or degradation of unfolded proteins. In this study, we constructed an ireA (IRE1 ortholog) conditionally expressing strain of Aspergillus oryzae, a filamentous fungus producing a large amount of amylolytic enzymes, and examined the contribution of UPR to ER stress adaptation under physiological conditions. Repression of ireA completely blocked A. oryzae growth under conditions inducing the production of hydrolytic enzymes, such as amylases and proteases. This growth defect was restored by the introduction of unconventional intronless hacA (hacA-i). Furthermore, UPR was observed to be induced by amylolytic gene expression, and the disruption of the transcriptional activator for amylolytic genes resulted in partial growth restoration of the ireA-repressing strain. In addition, a homokaryotic ireA disruption mutant was successfully generated using the strain harboring hacA-i as a parental host. These results indicated that UPR is required for A. oryzae growth to alleviate ER stress induced by excessive production of hydrolytic enzymes.
...
PMID:Unfolded protein response is required for Aspergillus oryzae growth under conditions inducing secretory hydrolytic enzyme production. 2649 81