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Biology 465 > Lecture 31 - 33: Autophagy > Flashcards

Lecture 31 - 33: Autophagy Flashcards

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1
Q

What are two types of cellular degradation machinery?

A
  • UPS (ubiquitin-proteosomal)

- Autophagy

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2
Q

How does UPS degrade cells?

A
  • Proteins are tagged by ubiquitin, which starts the downstream activation of then enzymes E1 (activation), E2 (conjugation) and E3 (ligation of ubiquitin to substrate)
  • Degradation occurs in the proteosome
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3
Q

What does autophagy degrade in cells?

A
  • Bulk degradation
  • Large organelles
  • Double-membraned vesicles
  • Degraded in the lysosome
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4
Q

What are the major types of autophagy?

A
  • Macroautophagy
  • Microautophagy
  • Chaperone-mediated autophagy
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5
Q

What are the different forms of autophagy based on the organelle it is digesting?

A
  • Mitophagy (mitochondria)
  • Pexophagy (peroxisome)
  • Lipophagy (lipid droplet)
  • Reticulophagy (ER)
  • Lysophagy (lysosome)
  • Nucleophagy (nucleus)
  • Rnautophagy (RNA)
  • Ribophagy (ribosome)
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6
Q

What did Professor Yoshinori Ohsumi discover during cell starvation.

A
  • Yeast was starved of nitrogen (PMSF) to see their behaviour
  • He treated them with a protease inhibitor which blocks proteases
  • As time proceeded, vacuoles began to appear which turned out to contain autophagic bodies
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7
Q

How is autophagy initiated?

A
  • Stress (such as starvation) causes a phagophore to form
  • The phagophore engulfs the cytosolic material to become autophagosome
  • The autophagosome fuses with a lysosome to generate a autophagolysosome
  • results in autophagy mediated degradation
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8
Q

What can autophagy degrade?

A
  • Bulk degradation of organelles, lipids and proteins
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9
Q

When the professor introduced mutations into the yeast cells and performed the same experiment, what occurred?

A

The vacuoles formed again but this time they were clear and empty as they lacked the autophagic bodies

  • also noticed a reduction of protein turnover
  • the mutants died in the absence of nitrogens as they had lost their viability
  • led to the discovery of a whole series of genes (Atg genes)
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10
Q

What are the three main stages of autophagy?

A
  1. Induction
  2. Elongation and maturation
  3. Fusion and clearance
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11
Q

Why is autophagy considered to have two ubiquitin-like conjugation systems?

A
  • In a stress situation, Atg genes form a complex with the help of the enzymes E1 and E2 which initiates the phagophore formation (starts with Atg12)
  • A second ubiquitin-like conjugation occurs as the membrane closes to form the autophagosome
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12
Q

How is induction regulated in nutrient rich conditions and starvation conditions?

A

In nutrient rich conditions, mTOR kinase inhibits the phosphatase that phosphorylates Atg13. Atg13 remains in a hyperphosphorylated state and cannot active downstream Atgs which results in the inhibition of autophagy.
In starvation conditions, mTOR is inactive and the phosphotase is active. The phosphatase dephosphorylates Atg13 which phosphorylates the Atgs downstream. Thus resulting in induction of autophagy.

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13
Q

How does the elongation and maturation step occur?

A

Atg8 (LC3) gets modified by E1 and E2 modification steps

- it results in membrane recruitment

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14
Q

How does fusion step occur?

A

The modified LC3B is inserted into the membrane

  • the membrane closes up and then fuses with the lysosome
  • Some of the Atg proteins and the target get degraded and return to the cell to be reused
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15
Q

What can be noted about the morphology of the autophagic body?

A

It is a double membrane structure that contains material being degraded

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16
Q

Where is LC3 located when autophagy is inhibited? Where is it located when the cell is starved?

A

Happy cell: within the cytosol
Starved cell: in the autophagosome membrane
- can be determined when cells are stained with green fluorescent protein

17
Q

What happens to LC3 when mTOR is inhibited?

A
  • Phosphatases are surpressed
  • LC3 is modified and the formation of the phagophore occurs
  • LC3 is inserted into the phagophore membrane
  • Lysosome fusion occurs and degrades the material
  • It can be used to measure the amount of autophagy in the cell
18
Q

At what points during autophagy pathway can you block with drugs?

A
  • During the elongation of the phagophore
  • You can inhibit the fusion of the lysosome and the autophagosome
  • You can inhibit mTOR
  • You can inhibit the formation of the autolysosome
19
Q

Why would you use p62?

A

p62 is a molecule that helps selects for cargo

  • if autophagy is blocked, no degradation occurs so p62 accumulates in the cell
  • it and LC3 are good indicators of how the cell is doing
20
Q

How would you test if a drug activates autophagy or not?

A

You would perform a autophagy flux assay

  • You treat the cell alone with a drug that is known to inhibit degradation or fusion
  • You then treat the cell with your drug
  • You then treat the cell with both drugs at the same time
21
Q

What are the consequences of autophagy?

A
  • Results in the degradation of materials to get the basic building blocks (lipids, carbohydrates, etc.)
  • Tumor cells can turn this system on when it starts to become stressed (from hypoxia, ROX, etc.) which results in building blocks that can feed and support the tumor cell and its neighbours
  • Glutamate
22
Q

How does autophagy lead to cell death?

A
  • When the cell is stressed, autophagy is activated and begins to degrade things until there is nothing left to degrade
  • The stress can lead to death through an autophagic dependent program
  • But the building blocks can keep the cell alive during autophagic cell death
23
Q

Why is autophagy in cancer considered to be a double edge sword?

A
  • When autophagy is non functioning, it leads to tumor initiation which means autophagy suppresses tumors
    • the cell becomes more unstable as things are unable to degrade
  • An increase of autophagy when proliferation is deregulated, leads to tumor promotion
    • tumors have more tolerance to stresses
24
Q

How does autophagy work in tumor suppression?

A

The cell has the ability to undergo autophagy

  • Proteins and organelles are damaged and p62 is induced which results in the activation of autophagy
  • The damaged proteins, organelles and p62 are degraded
  • The cell is no longer stressed and is stable thus the tumor is suppressed
25
Q

What occurs to a cell if autophagy is inactive and the cell becomes stressed?

A

The cell undergoes damages to proteins and organelles, p62 induction and other situations that increases genomic instability (ROS production, hypoxia, etc.)

  • Since there is no degradation of the cells, tissue damage and mutations form
  • Thus the tumor is initiated
26
Q

If a tumor has initiated and autophagy is functional, what happens?

A

The tumor grows until it reaches a certain mass where it becomes stressed (from hypoxia, for example)

  • The functional autophagy helps assist in the stress by degrading certain organelles
  • Ultimately the cell survives until the conditions improve and continues to grow
27
Q

If a tumor is initiated and autophagy is defective, what happens to the tumor?

A

The tumor cell begins to grow until it reaches a certain mass where it becomes stressed

  • Some of the cells stop proliferating and others die
  • As there is no autophagy, there is nothing to help keep the cell alive
  • This results in growth arrest, cell death and tumor atrophy
28
Q

What stages in the pathway do the autophagy inhibitors block?

A
  • Some can block the whole pathway
  • Some can block the signalling that results in the formation of the phagophore
  • Some can block the fusion of the lysosome and the autophagosome
  • Some block the first step before the cascade can be initiated (block the activation of mTOR)
  • Only the drug that inhibits lysosome fusion works well in animals
29
Q

When inhibiting autophagy to treat tumors, what worked better? Treating with one drug or treating with a mixture?

A

Treating with a mixture

  • there was a decrease in tumor size
  • there was increases in progression free survival

Biology 465 (15 decks)

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