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Role of the unfolded protein response in regulating the mucin-dependent filamentous-growth mitogen-activated protein

Hema Adhikari1, Nadia Vadaie1, Jacky Chow1

  • 1Department of Biological Sciences at SUNY-Buffalo, Buffalo, New York, USA.

Molecular and Cellular Biology
|February 11, 2015
PubMed

Insights

Underglycosylation of the signaling mucin Msb2p triggers its cleavage via the unfolded protein response (UPR), a cellular quality control pathway. This processing is essential for yeast filamentous growth and cell differentiation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Signaling mucins, like Msb2p in yeast, are crucial regulators of signal transduction pathways.
  • Msb2p controls the Cdc42p-dependent mitogen-activated protein kinase (MAPK) pathway, which governs filamentous growth.
  • Activation of the MAPK pathway by Msb2p necessitates the cleavage and release of its inhibitory glycosylated domain.

Purpose of the Study:

  • To investigate the regulatory mechanisms controlling Msb2p cleavage.
  • To elucidate the role of protein glycosylation and quality control pathways in Msb2p processing.
  • To understand how Msb2p processing influences yeast cell differentiation and filamentous growth.

Main Methods:

  • Investigated Msb2p processing in yeast underglycosylation mutants.
  • Utilized conditional trafficking mutants to study Msb2p localization and processing.
  • Examined the role of the unfolded protein response (UPR) and its regulator Ire1p in Msb2p cleavage.
  • Assessed the impact of Msb2p turnover by Rsp5p and ESCRT on signaling pathways.

Main Results:

  • Proteolytic processing of Msb2p is induced by underglycosylation of its extracellular domain.
  • Cleavage of underglycosylated Msb2p depends on the unfolded protein response (UPR) operating in the endoplasmic reticulum (ER).
  • The UPR regulator Ire1p controls Msb2p cleavage by modulating the transcription of the protease Yps1p.
  • UPR is necessary for differentiation into the filamentous cell type.
  • Processed Msb2p is trafficked to the plasma membrane, where its degradation by Rsp5p and ESCRT attenuates filamentous growth.

Conclusions:

  • Underglycosylation serves as a trigger for Msb2p processing through the UPR-mediated quality control pathway.
  • The UPR pathway integrates protein folding status with signaling pathway activation, impacting cell differentiation.
  • Quality control pathways may broadly regulate signaling glycoproteins by sensing aberrant glycosylation patterns, potentially in response to environmental cues.

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