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ER stress causes widespread protein aggregation and prion formation
Norfadilah Hamdan1, Paraskevi Kritsiligkou1, Chris M Grant2
1Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, England, UK.
The Journal of Cell Biology
|June 21, 2017
Summary
Endoplasmic reticulum (ER) stress disrupts cellular protein balance, causing widespread protein aggregation. Enhancing cellular protein quality control mechanisms can mitigate this aggregation and protect against ER stress.
Area of Science:
- Cellular Biology
- Molecular Biology
- Biochemistry
Background:
- Endoplasmic reticulum (ER) homeostasis is crucial for cellular function.
- Disturbances in ER homeostasis lead to a state known as ER stress.
- ER stress activates the unfolded protein response (UPR) to restore homeostasis.
Purpose of the Study:
- To investigate the consequences of ER stress on protein homeostasis.
- To identify the types of proteins affected by ER stress-induced aggregation.
- To explore potential protective mechanisms against ER stress-related protein aggregation.
Main Methods:
- Induction of ER stress in cellular models.
- Proteomic analysis to identify aggregated proteins.
- Investigation of the role of proteasome and chaperones in protein aggregation.
- Assessment of UPR mutant responses to ER stress.
Main Results:
- ER stress induces aggregation of proteins, predominantly those intrinsically prone to aggregation, not specific to the ER or secretory pathway.
- Protein aggregation is a consequence of general disruption in cellular protein homeostasis, not solely due to proteasome overload.
- Overexpression of specific chaperones reduces protein aggregation and confers protection to UPR-mutant cells under ER stress.
Conclusions:
- ER stress leads to widespread amorphous and amyloid protein aggregation as an unexpected outcome.
- Protein aggregation during ER stress is linked to a broader failure of cellular protein quality control.
- Chaperone-mediated protein quality control is a potential therapeutic target for ER stress-related disorders.
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