Coupling the MAPK Slt2/ERK1 Pathway and IRE1-driven UPR Through Transcription Factor Rlm1/MEF2

TL;DR

This study reveals a new connection between the UPR and MAPK pathways through the Rlm1/MEF2 transcription factor in yeast.

Contribution

The novel crosstalk between the MAPK pathway and IRE1-driven UPR via Rlm1/MEF2 is identified.

Findings

The UPR has two phases: an early IRE1-dependent phase and a later phase involving Slt2/ERK1 and Rlm1/MEF2.

Slt2 promotes IRE1 expression through Rlm1, revealing a new regulatory mechanism.

Rlm1/MEF2 is a downstream target of Slt2/ERK1 and contributes to UPR regulation.

Abstract

Unfolded protein response (UPR) is a conserved cellular strategy that enhances the protein folding capacity of cells under stress conditions. In Saccharomyces cerevisiae, the dual kinase RNase IRE1 initiates the UPR by catalyzing the cytosolic splicing of HAC1 mRNA, a process conserved in humans where IRE1 splices XBP1 mRNA. The spliced HAC1/XBP1 mRNA yields a transcription factor that upregulates the expression of protein-folding enzymes and chaperones, thereby boosting the cell’s ability to cope with unfolded proteins. Our study demonstrates that the UPR involves two distinct phases. The early phase operates predominantly through the canonical IRE1 signaling pathway, while the later phase involves additional regulation by the MAP kinase Slt2 or its human ortholog ERK1/ERK2/ERK5 and the downstream target the MADS-box transcription factor Rlm1 (an ortholog of human MEF2C). We further show that Slt2 promotes IRE1 expression through Rlm1. Together, these findings reveal a previously unrecognized crosstalk between the MAPK and IRE1-mediated arm of the UPR.

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