Abstract
Hac1p is a key transcription factor regulating the unfolded protein response (UPR) induced by abnormal accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) in Saccharomyces cerevisiae. The accumulation of unfolded/misfolded proteins is sensed by protein Ire1p, which then undergoes trans-autophosphorylation and oligomerization into discrete foci on the ER membrane. HAC1 pre-mRNA, which is exported to the cytoplasm but is blocked from translation by its intron sequence looping back to its 5’UTR to form base-pair interaction, is transported to the Ire1p foci to be spliced, guided by a cis-acting bipartite element at its 3’UTR (3’BE). Spliced HAC1 mRNA can be efficiently translated. The resulting Hac1p enters the nucleus and activates, together with coactivators, a large number of genes encoding proteins such as protein chaperones to restore and maintain ER homeostasis and secretary protein quality control. This review details the translation regulation of Hac1p production, mediated by the nonconventional splicing, in the broad context of translation control and summarizes the evolution and diversification of the UPR signaling pathway among fungal, metazoan and plant lineages.
Highlights
Translation control occurs at different levels, with global and specific regulation as two extremes of the continuum
The key genes involved in unfolded protein response (UPR) signaling in the yeast are IRE1 and HAC1, together with genes such as TRL1 that helps ligate cleaved HAC1 exons into a processed and efficiently translatable mRNA (Figure 2)
There is, little sequence homology between yeast HAC1 and mammalian Xbp1, either at the nucleotide or amino acid level, except for a short stretch in the protein sequence that is rich in positively charged amino acids corresponds to sites 29-53 in the yeast Hac1p
Summary
Translation control occurs at different levels, with global and specific regulation as two extremes of the continuum. This results in a shorter protein (Hac1up) missing the activation domain encoded in the second exon. This base-pair interaction would interfere with the cap-dependent scanning by the small ribosomal subunit to find the start codon. Di Santo et al [33] provided direct experimental evidence to demonstrate that the polysome-like sedimentation of HAC1u is not due to ribosomes translating HAC1u, but is due to non-specific association between HAC1u and other actively translated mRNAs
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