HacA-Dependent Transcriptional Switch Releases hacA mRNA from a Translational Block upon Endoplasmic Reticulum Stress

ABSTRACTActivation 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. InSaccharomyces cerevisiaea 252-nucleotide (nt) unconventional intron is spliced out of the transcript ofHAC1, changing the 3′ end of theHAC1open 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). InAspergillus nigerand other aspergilli, the unconventional intron inhacAmRNA 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 yeastHAC1, is not possible. However, analysis of thehacAmRNA revealed a GC-rich inverted repeat (18 base pairings). Upon the activation of the UPR, the 5′UTR ofhacAmRNA 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 ofS. cerevisiae HAC1but in two steps. The mechanism behind the 5′ truncation, which does not take place in either yeastHAC1or mammalianxbp1mRNA, has been hitherto unknown. Here we show that during secretion stress inA. niger,hacAtranscription 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 thehacApromoter.