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Cellular and Molecular > Lecture 20- Autophagy I > Flashcards

Lecture 20- Autophagy I Flashcards

1
Q

What is the purpose of autophagy?

A

To digest intracellular material

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2
Q

Outline the mechanism of autophagy

A
  1. Initiation of a new vesicle and the formation of a phagophore
  2. Expansion: the phagophore elongates and a double membrane autophagosome forms to enclose cellular components
  3. Fusion: the autophagosome fuses with the lysosome (containing degradative machinery)
  4. Acidification and maturation
  5. Autolysosome components are degradated and recycled
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3
Q

Why do cells need degradation?

A
  1. Homeostasis
  2. Signalling
  3. Removing damaged components
  4. Recycling nutrients
  5. Reprogramming cells (differentiation)
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4
Q

What are the 3 types of autophagy?

A
  1. Macroautophagy
  2. Chaperone-mediated autophagy
  3. Microautophagy
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5
Q

Briefly explain how material is degraded by UPS?

A

Proteins get ubiquitinated by E1/2/3 or DUBs and targeted to the proteasome to be eliminated

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6
Q

Briefly explain the mechanism of macroautophagy

A
  1. Main degradation pathway
  2. Cytoplasmic cargo is delivered to the lysosome through an intermediary double membrane bound vesicle (autophagosome)
  3. The autophagosome fuses with the lysosome to form an autolysome
  4. Acidification and maturation occurs
  5. Finally, the cargo is degredated and the material recycled
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7
Q

Briefly explain chaperone-mediated autophagy

A
  1. Involved the direct translocation of cytoplasmic proteins across the lysosomal membrane in a complex with chaperone proteins
  2. The chaperone proteins on the complex get recognised by lysosomal membrane receptor (LAMP-2A)
  3. Resulting in their unfolding and degradation
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8
Q

Briefly outline microautophagy

A
  1. Direct engulfment of cytoplasmic cargo into the lysosome

2. Occurs through the invagination of the lysosomal membrane

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9
Q

What are the 4 main functions of macroautophagy?

A
  1. Nutrient recycling
  2. Cellular remodelling
  3. Removal of damaged components
  4. Killing intracellular pathogens
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10
Q

Explain the function of nutrient recycling in macroautophagy

A
  1. Autophagy is rapidly upregulated under starvation
  2. Causes non-selective bulk degradation of the cytosol
  3. Cells lacking autophagy (atgl mutants) die under starvation
  4. Autophagy deficient (gene KO) mice die due to starvation
  5. Cancer cells in solid tumour need autophagy to survive
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11
Q

Explain the function of cellular remodelling in autophagy

A
  1. Autophagy is the ONLY mechanism to degrade organelles

2. So is essential to form some specific cell types

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12
Q

Give 2 examples where autophagy is is required for cellular remodelling

A
  1. Erythropoiesis: autophagy is the main method of mitochondrial clearance to form mature erythrocytes
  2. Removal of sperm-derived mitochondria: autophagy removes sperm-derived mitochondria to ensure only maternal inheritance of mitochondria occurs
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13
Q

Explain the function of removing damaged components by autophagy

A

Cellular components accumulate damage over time so autophagy is needed to remove these damaged components

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14
Q

Give 2 examples where autophagy is required for removal of damaged components

A
  1. Mitochondria damage: autophagy selectively targets and removed damaged mitochondria after exercise
  2. Ageing/neurodegenerative diseases: cells continuously acquire damage.

Lysosomal capacity decreases as we age so our immune cells get less efficient. Reduced autophagy is the major reason for age-related degeneration

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15
Q

What is the dietary restriction hypothesis?

A

That starvation/exercise stimulates autophagy and increases damage repair

Thus making you live longer

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16
Q

What proof has there been that the dietary hypothesis works?

A

Eat2 mutants have a pharyngeal distinction (show starvation) and survive longer than wildtypes

17
Q

What 2 pathways regulate caloric restriction?

A

TORC1 and AMPK/SIRT1 pathways and leads to increase life span/rescues disease

18
Q

Explain the function of killing intracellular pathogens by autophagy

A

Many pathogens escape into the cytoplasm, prevent fusion with lysosomes or survive in phagolysosome

If they do escape into the cytosol, bacteria can be recognised and targeted by autophagosome where the attempt again to kill the intracellular pathogen

19
Q

What did the identification of Atg genes allow?

A
  1. Disruption of autophagy to investigate its function
  2. Start on dissecting how the machinery works
  3. Observe autophagy in live cells (e.g GFP-Atg8)
20
Q

What are the 4 main regulatory complexes involved in autophagy machinery?

A
  1. ULK1 complex
  2. P13K/Vps34 complex
  3. Complex of ubiquitin ligase reactions
  4. Specific SNAREs
21
Q

What is the role of ULK1 complex in autophagy?

A
  1. A kinase which is regulated by AMPK and mTORC1
  2. If you activate ULK1 complex, it will activate kinase activity which directly phosphorylates parts of the second complex P13K/Vps34
  3. Responds to signals which turns it on/off
22
Q

What is the role of P13K/Vps34 complex in autophagy?

A

Starts to initiate autophagosome formation

23
Q

What is the role of the complex of ubiquitin ligase reactions in autophagy?

A

Allows the delivery and expansion of the membrane

24
Q

What is the role of SNAREs in autophagy?

A
  1. Recognised the lysosome and fuses them to autophagosomes

2. Mediates the final closure of the autolysosomes

25
Q

Describe the selective autophagy mechanism

A
  1. Autophagosomes are coated in Atg8 (or LC3)
  2. Adaptor proteins have Atg8 interaction motif which binds specifically and UBD which binds to organelles
  3. The binding ensures components are dragged specifically into the autophagosome
  4. Therefore you can use ubiquitin tags to selectively transport components into the autophagosome
  5. Also, the individual proteins have their own AIM which bind to the inside of the autophagosome

Cellular and Molecular (24 decks)

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