Lecture 16: Cell Stress

Question 1

What is cellular stress?

Answer 1

a condition perceived by the cell as a threat to homeostasis

homeostasis is the equilibrium where cellular functions are optimal

Question 2

3 functions of heat shock protein

Answer 2

binds to unfolded proteins and

1. minimize denaturation
2. prevent protein aggregation
3. facilitate refolding

Question 3

Nrf2 and Keap1

Answer 3

ROS sensor

Nrf2 normally sequestered in cytoplasm by Keap1

Keap1 promotes proteasomal degradation of Nrf2

phosphorylation of Keap1 lowers the affinity for Nrf2

Nrf2 stabilized, accumulates and translocate to nucleus

Question 4

3 Nrf2 induced genes

Answer 4

1. Heme oxygenase 1
2. Glutathione A2
3. NAD(P)H quinone oxidoreductase (NQO1)

Question 5

HIF signalling

Answer 5

hypoxic sensor

decrease in oxygen

oxygen is essential for energy production because it is the terminal electron acceptor in the electron transport chain of the mitochondria

Question 6

Hypoxic stress response/HIF signalling under normoxia

Answer 6

Prolyl hydroxylases (PHD) catalyze irreversible hydroxylation of proline residue on HIF-1A

VHL degrades HIF-1a by proteasomal degradation

HIF-1a kept at low/inactive concentration

Question 7

HIF stress response under hypoxia

Answer 7

lack of oxygen impaired PHD activity (not enough oxygen for hydroxylation)

HIF-1a stabilize and accumulates

dimerize with HIF-B subunit

binds DNA and transcribe hypoxia response elements (HREs)

Question 8

What is ER stress?

Answer 8

disruption of a cell’s ability to produce properly folded proteins

glucose deprivation: inhibit N-linked glycosylation

abbreant Ca homeostasis

viral infection: hijacked by virus to produce viral proteins

Question 9

PERK pathway

Answer 9

activated PERK phosphorylate eIF2a and lead to general translational suppression

activates ATF4

can also directly phosphorylate and activate NRF2 to express anti-oxidant genes

Question 10

IRE1a pathway

Answer 10

activated IRE1a cleaves mRNA encoding for XBP1 (affect splicing)

Cleaved XBP1 proteins promote expression of ER-stress responsive genes

Question 11

ATF6 pathway

Answer 11

ATF6 is cleaved by SP1 and SP2 in response to ER stress

Cleaved N-terminal factor increase transcription of UPR target genes with XBP1 and ATF4

upregulated BiP and GADD153

Question 12

BiP

Answer 12

cellular stress sensor to activate IRE1a, PERK and ATF6 response to upregulate UPR gene transcription