Specificity in endoplasmic reticulum-stress signaling in yeast entails a step-wise engagement of HAC1 mRNA to clusters of the stress sensor Ire1

eLife

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