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Purification of the Membrane Compartment for Endoplasmic Reticulum-associated Degradation of Exogenous Antigens in Cross-presentation
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Selective clearance of aberrant membrane proteins by TORC1-mediated micro-ER-phagy

Valeriya Gyurkovska1, Yaneris M Alvarado Cartagena1, Rakhilya Murtazina1

  • 1Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.

Cell Reports
|February 13, 2025
PubMed

Insights

Nutritional stress clears misfolded membrane proteins via a specific pathway in yeast. This discovery suggests a potential therapeutic strategy for clearing disease-associated proteins.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Aberrant accumulation of membrane proteins is linked to various diseases.
  • The endoplasmic reticulum (ER) is the initial site for membrane protein insertion and quality control (QC).
  • Two primary QC pathways, ER-associated degradation and macro-ER-phagy, target misfolded or excess proteins for degradation.

Purpose of the Study:

  • To investigate the mechanisms of membrane protein clearance during cellular stress.
  • To determine the role of different stress conditions in activating ER-QC pathways.
  • To identify potential therapeutic strategies for clearing disease-associated membrane proteins.

Main Methods:

  • Utilized yeast as a model organism to study ER-QC.
  • Compared protein clearance under normal growth conditions versus nutritional, proteotoxic, and heat stress.
  • Investigated the molecular players involved in the micro-ER-phagy pathway, including Rsp5, Ssh4, and ESCRT.

Main Results:

  • ER-QC is constitutive and not dependent on stress-induced signaling pathways during normal growth.
  • Nutritional stress, but not proteotoxic or heat stress, activates clearance of accumulated proteins in ER-QC mutants.
  • Selective micro-ER-phagy, dependent on Rsp5, Ssh4, and ESCRT, clears proteins early during nutritional stress.
  • Macro-autophagy degrades a fraction of normal membrane proteins much later.

Conclusions:

  • Nutritional stress triggers a conserved, selective pathway for clearing misfolded membrane proteins.
  • This pathway, involving micro-ER-phagy, offers a potential therapeutic avenue for diseases linked to membrane protein accumulation.
  • Understanding these conserved mechanisms is crucial for developing treatments for proteinopathies.
Keywords:
CP: Cell biologyER-quality controlERADEndoplasmic reticulumHSRTORC1UPRmacro-ER-phagymicro-ER-phagynutritional stress

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