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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.

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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.

Keywords:
Endoplasmic reticulum stress (ER stress)Extracellular-signal-regulated kinase (ERK)HAC1 mRNAIRE1 (Inositol requiring enzyme 1)Mitogen-activated protein kinase (MAPK)Protein kinaseSlt2Unfolded protein response (UPR)

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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.