eLife | |
Specificity in endoplasmic reticulum-stress signaling in yeast entails a step-wise engagement of HAC1 mRNA to clusters of the stress sensor Ire1 | |
David Pincus1  Federica Lari2  Scott Coyle3  Silvia Gómez Puerta3  Christof Osman3  Tomás Aragón4  Peter Walter5  Eelco van Anken6  Alexei V Korennykh6  | |
[1] Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States;Department of Gene Therapy and Gene Regulation, Center for Applied Medical Research, Pamplona, Spain;Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States;Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States;Department of Gene Therapy and Gene Regulation, Center for Applied Medical Research, Pamplona, Spain;Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy; | |
关键词: stress signaling; endoplasmic reticulum; unfolded protein response; mRNA targeting; mRNA processing; | |
DOI : 10.7554/eLife.05031 | |
来源: DOAJ |
【 摘 要 】
Insufficient protein-folding capacity in the endoplasmic reticulum (ER) induces the unfolded protein response (UPR). In the ER lumen, accumulation of unfolded proteins activates the transmembrane ER-stress sensor Ire1 and drives its oligomerization. In the cytosol, Ire1 recruits HAC1 mRNA, mediating its non-conventional splicing. The spliced mRNA is translated into Hac1, the key transcription activator of UPR target genes that mitigate ER-stress. In this study, we report that oligomeric assembly of the ER-lumenal domain is sufficient to drive Ire1 clustering. Clustering facilitates Ire1's cytosolic oligomeric assembly and HAC1 mRNA docking onto a positively charged motif in Ire1's cytosolic linker domain that tethers the kinase/RNase to the transmembrane domain. By the use of a synthetic bypass, we demonstrate that mRNA docking per se is a pre-requisite for initiating Ire1's RNase activity and, hence, splicing. We posit that such step-wise engagement between Ire1 and its mRNA substrate contributes to selectivity and efficiency in UPR signaling.
【 授权许可】
Unknown