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ER signaling in unfolded protein response
Masayuki Kaneko1, Yasuyuki Nomura
1Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, 060-0812, Sapporo, Japan.
Life Sciences
|November 11, 2003
Summary
The unfolded protein response (UPR) protects cells from death by degrading misfolded proteins. Human HRD1 and SEL1 genes are activated by the UPR and help degrade these toxic proteins, preventing cell death.
Area of Science:
- Cellular Biology
- Molecular Biology
- Biochemistry
Background:
- Abnormally folded proteins can aggregate and cause cell death.
- The unfolded protein response (UPR) activates cellular defense mechanisms, including ER-associated protein degradation (ERAD), to clear unfolded proteins from the endoplasmic reticulum (ER).
- ERAD involves retrotranslocation of unfolded proteins to the cytosol for proteasomal degradation.
Purpose of the Study:
- To identify and characterize human homologs of the yeast ERAD components Hrd1p and Hrd3p.
- To investigate the role of human HRD1 and SEL1 in the UPR and their contribution to cellular protection against ER stress.
Main Methods:
- Isolation and identification of human HRD1 and SEL1 genes.
- Analysis of HRD1 and SEL1 gene expression in response to ER stress and UPR-inducing factors (IRE1, ATF6).
- Assessment of cell viability in HEK293T cells overexpressing HRD1 under ER stress conditions.
Main Results:
- Human homologs HRD1 (ubiquitin ligase) and SEL1 (Hrd1p stabilizer) were identified.
- HRD1 and SEL1 expression increased upon ER stress and overexpression of IRE1 and ATF6.
- Overexpression of HRD1 conferred resistance to ER stress-induced cell death in HEK293T cells.
Conclusions:
- HRD1 and SEL1 are upregulated by the UPR.
- These genes play a protective role against ER stress-induced cell death.
- HRD1 and SEL1 contribute to the degradation of unfolded proteins accumulated in the ER.