Coupling the MAPK Slt2/ERK1 Pathway and IRE1-driven UPR Through Transcription Factor Rlm1/MEF2
Madhusudan Dey1, Anish Chakraborty1, Saswata Chakrabarty1
1Department of Biological Sciences, UW-Milwaukee, WI-53211.
Research Square
|January 9, 2026
Summary
The unfolded protein response (UPR) has two phases. A later phase involves MAP kinase Slt2 and transcription factor Rlm1, revealing crosstalk between MAPK and IRE1 pathways.
Area of Science:
- Cellular Biology
- Molecular Biology
- Biochemistry
Background:
- The unfolded protein response (UPR) is a critical cellular mechanism for managing protein folding stress.
- IRE1 RNase is a key initiator of UPR, splicing HAC1 mRNA in yeast and XBP1 mRNA in humans.
- Spliced mRNA generates transcription factors that upregulate protein-folding enzymes and chaperones.
Purpose of the Study:
- To investigate the distinct phases and regulatory mechanisms of the UPR.
- To identify novel components and pathways involved in the later stages of UPR.
- To elucidate the crosstalk between different signaling pathways within the UPR.
Main Methods:
- Utilized Saccharomyces cerevisiae as a model organism.
- Investigated the roles of MAP kinase Slt2 and transcription factor Rlm1 in UPR.
- Analyzed the regulation of IRE1 expression by Slt2 and Rlm1.
Main Results:
- Demonstrated that UPR proceeds in two distinct phases: an early IRE1-canonical phase and a later phase involving Slt2 and Rlm1.
- Showed that Slt2 (or its human orthologs ERK1/ERK2/ERK5) and Rlm1 (or human MEF2C) are involved in the later UPR phase.
- Established that Slt2 promotes IRE1 expression via Rlm1, indicating a novel regulatory loop.
Conclusions:
- The UPR involves a previously unrecognized crosstalk between the MAPK pathway (via Slt2) and the IRE1-mediated pathway.
- This crosstalk, involving Slt2 and Rlm1, contributes to the regulation of the UPR, particularly in its later stages.
- Findings expand our understanding of cellular stress response and adaptive mechanisms.
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