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Cell Proliferation and Survival Mechanisms Underlying Disease > Nrf2 > Flashcards

Nrf2 Flashcards

- What is Nrf2, how is it regulated, and why does it promote cell survival - What are cyanoenone triterpenoids - How do cyanoenone triterpenoids activate Nrf2 - What is the evidence that Nrf2 protects against inflammation - What is itaconate and how does it activate Nrf2 - That Nrf2 is inactivated in certain viral infections - The effect of pharmacological Nrf2 acrtivators in viral infections

1
Q

Nrf2

A
  • normally bound to Keap1, which targets Nrf2 for ubiquitination and degradation by the proteasome
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2
Q

What is Nrf2

A
  • TF
  • regulates the cellular defense against toxic and oxidative insults
  • regulates redox homeostasis
  • involved in cellular processes e.g. metabolism and inflammation
  • binds to ARE
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3
Q

How is Nrf2 regulated?

A
  • complex transcriptional and post-translational network
  • adaptation to various pathological stressors to maintain homeostasis
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4
Q

How does Nrf2 promote cell survival?

A

1) Antioxidant effects
2) Detoxification
3) Inflammation suppression
4) Proteostasis

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5
Q

How does Nrf2 exhibit antioxidant effects

A

activates SOD, catalase, glutathione peroxidase, and heme oxygenase-1 (HO-1); scavenge ROS and other free radicals that cause oxidative damage to cellular macromolecules

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6
Q

How does Nrf2 exhibit detoxification effects

A

regulates expression of phase II detoxification enzymes (e.g. GSTs, UGTs, NQO1); which conjugate and eliminate electrophilic xenobiotics and endogenous metabolites that can damage DNA

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7
Q

How does Nrf2 suppress inflammation

A

inhibits expression of pro-inflammatory cytokines and chemokines (IL-1B, IL-6, TNF-a, COX-2); reduces tissue damage and promotes tissue repair

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8
Q

Role of Nrf2 in proteostasis

A

regulates expression of molecular chaperones (HSPs) and proteasomal subunits that maintain protein folding and degradation; Nrf2 protects cells from apoptosis

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9
Q

Role of Nrf2 in redox homeostasis

A

Glutathione and thioredoxin biosynthesis and utilisation via positive regulation of:
- Glutathione S-transferases
- y-Glutamylcysteine synthestase
- Glutathione reductase 1
- Thioredoxin
- Thioredoxin reductase

NADPH regeneration and utilisation via positive regulation of:
- Malic enzyme 1
- Isocitrate dehydrogenase 1
- 6-Phosphogluconate dehydrogenase
- Glucose-6-phosphate dehydrogenase

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10
Q

Keap1 sensor

A
  • cystine based
  • suppresses Nrf2 transcriptional activity
  • specifically binds Nrf2 to the amino-terminal regulatory domain
  • antagonised by electrophilic agents
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11
Q

How do electrophilic inducers affect the Keap1 cycle

A
  • disrupt the cycle by modifying sensor cysteines of Keap1, preventing Nrf2 ubiquitination and Keap1 regeneration
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12
Q

NQO1

A
  • two-electron reductase responsible for detoxification of quinones and also bioactivation of certain quinones
  • abnormally overexpressed in tumours
  • intimately linked with carcinogenic processes
  • selective anticancer therapy
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13
Q

What are cyanoenone triterpenoids

A
  • potent users of NQO1 and Nrf2
  • semi-synthetic derivatives
  • abundant in plants
  • used in wound dressing due to weak anti-inflammatory activity
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14
Q

Explain the linear correlation between suppression in the iNOS and the induction of NQO1

A

by activating Nrf2, we can suppress inflammation

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15
Q

Persistent activation of Nrf2

A
  • promotes the progression of cancer
  • promotes treatment resistance
  • triggered by Keap1-inactivating mutations
  • triggered by mutations in ETGE and DLG motifs
  • triggered by epigenetic silencing of Keap1/disruption of Nrf2-Keap1 interaction
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16
Q

Transient activation of Nrf2

A

protect against cancer development

17
Q

Nrf2 activators

A
  • oltipraz (OPZ)
  • curcumin (CUR)
  • promote functions of antioxidants, phase II detoxification factors, and transducers
18
Q

Nrf2 inhibitors

A
  • luteolin
  • ascorbic acid (AScA)
  • trigonelline (Trg)
  • downregulate drug detoxification/elimination enzymes
  • sensitize cancer cells to chemotherapy
19
Q

How do cyanoenone triterpenoids activate Nrf2

A

1) Keap1/Nrf2 dissociation: cyanoenone triterpenoids can covalently modify cysteine residues in Keap1, causing a conformational change disrupting the KEap1/Nrf2 interaction; preventing Nrf2 degradation

2) Nuclear translocation of Nrf2: once Nrf2 has dissociated from Keap1, it is transported to the nucleus; cyanoenone triterpenoids enhance Nrf2 nuclear accumulation by activating PKC pathway, phosphorylating Nrf2 and promoting nuclear translocation

3) Co-activator recruitment: in the nucleus, Nrf2 recruits CBP and p200 (co-activators), facilitating transcription of ARE-containing genes. Cyanoneone triterpenoids can enhance co-activator recruitment by increasing the acetylation of histones, promoting chromatin remodelling and facilitating transcription

20
Q

What is the evidence that Nrf2 protects against inflammation

A
  • genetic activation of Nrf2 protects against SSUV radiation-mediated inflammation
21
Q

What is itaconate

A
  • acid that is transported to cytoplasm using citrate transporter
  • produced by activation of Irg1
  • promotes anti-inflammatory
  • can inhibit bacterial invastion as it can inhibit activity in bacteria
  • weakly electrophilic
  • involved in LPS-mediated stabilisation of nrf2
22
Q

How does itaconate activate Nrf2

A
  • via alkylation of Keap1
  • 4-octyl itaconate activates nrf2 by causing 2,3-dicarboxypropylation of Keap1
  • C151 is a sensor for 4-octyl itaconate
  • Nrf2 activation potentiates macrophage response to LPS, favouring pathogen inactivation whilst attenuating IL1beta pro-inflammatory signalling
23
Q

Nrf2 in viral infections

A
  • Nrf2 is suppressed by COVID-19
  • at later stage of infection strongly infected cells have high nrf2 activity as cells are using nrf2 to survive
24
Q

What is the pharmacological effect of Nrf2 activators in viral infections

A

measure release of viral DNA

25
Q

Nrf2 in glutathione and thioredoxin biosynthesis and utilization

A

positively regulates:
- glutathione S-transferases
- y-Glutamylcysteine synthetase
- Glutathione reductase 1
- Thioredoxin
- Thioredoxin reductase

26
Q

Nrf2 in NADPH regeneration and utilisation

A

positively regulates:
- malic enzyme 1
- isocitrate dehydrogenase 1
- 6-phosphogluconate dehydrogenase
- glucose-6-phosphate dehydrogenas

27
Q

Nrf2 in carbohydrate metabolism

A

positively regulates:
- UDP-glucose dehydrogenase
suppresses:
- pyruvate kinase
- glycerol phosphate dehydrogenase 2

28
Q

Nrf2 in lipid metabolism

A

suppresses:
- ATP citrate lyase
- acteyl-coenzyme A carboxylase
- fatty acid synthase
- stearoyl-coenzyme A desaturase
- lipase

29
Q

Nrf2 in amino acid metabolism

A

positively regulates:
- serine/glycine biosynthesis enzymes (PHGDH, PSAT1, SHMT2 via ATF4)

30
Q

Nrf2 in pentose phosphate pathway / nucleotide metabolism

A

positively regulates:
- glucose-6-phosphate dehydrogenase
- 6-phosphogluconate dehydrogenase
- transaldolase
- transketolase

Cell Proliferation and Survival Mechanisms Underlying Disease (11 decks)

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