Lecture 9

Question 1

When is the Unfolded Protein Response (UPR) induced?

Answer 1

When there is an accumulation of unfolded, misfolded, insoluble, or otherwise damaged proteins

Question 2

How can cells respond to the UPR?

Answer 2

By inducing apoptosis if stress is excessive or by increasing the production of chaperones (e.g., GRP78) if stress is minimal or by shutting down or slowing down the rate of translation into the ER

Question 3

What has GRP78 been shown to do?

Answer 3

Increase in breast cancer cells and protects cells from chemotherapy drugs

Question 4

What does constant ER stress (UPR) lead to?

Answer 4

Cell signals that increase inflammation and apoptosis (cell and tissue)

Question 5

What diseases have UPR associations?

Answer 5

• Diabetes - UPR-related cell death kills insulin-producing cells
• Neurological - UPR stress leads to cell death and nerve cell apoptosis
• Autoimmune - UPR stress in various cell types can increase inflammation

Question 6

How does UPR work?

Answer 6

By activating three different types of signal pathways to enable the ER to better handle protein translation and folding during ER stress

Question 7

What are the UPS sensors?

Answer 7

• IRE1
• PERK1
• RTF6

Question 8

What is IRE1?

Answer 8

Transmembrane protein kinase with cytoplasmic kinase and RNAse
- Binding of misfolded proteins in ER activates kinase and RNAse domain
- Causes splicing of pre-mRNA that produces unique transcription factors that turn on genes to expand the ER so that the protein folding capacity and protein degradation of misfolded proteins is increased

Question 9

What is PERK1?

Answer 9

Transmembrane protein kinase that phosphorylates translation factors (inhibiting overall protein synthesis)

Question 10

What is ATF6?

Answer 10

Transmembrane transcription factor that is cleaved when activated in golgi and turns on genes that can increase protein folding

Question 11

What happens in the IRE1 unfolded protein response (steps)?

Answer 11

1) Misfolded proteins in ER signal the need for more ER chaperons. They bind to and activate a transmembrane kinase.
2) Activated kinase unmasks an endoribonuclease activity
3) Endoribonuclease cuts specific RNA molecules at 2 positions, removing an intron
4) 2 exons are ligated to form an active mRNA
5) mRNA is translated to make a transcription regulator
6) Transcription regulator enters the nucleus and activates genes encoding ER chaperones
7) Chaperons are made in ER, where they help fold proteins