Autophagy

Question 1

Lysosomes function:

Answer 1

degrade & recycle macromolecules

Question 2

Functions for macroautophagy

Answer 2

1. Re-cycle proteins and other macromolecules under conditions of nutrient deprivation- allow recycling of amino acids, nucleotides and fatty acids.
2. Remove organelles- mitochondria and peroxisomes.
3. Allow cell survival under stress conditions (growth factor deprivation, hypoxia etc.)
4. Present antigens to MHC system
5. Neuro-protection- e.g. remove protein aggregates to prevent neuronal damage in e.g. Huntington’s, Parkinson’s disease etc.
6. Remove intracellular pathogens
7. Aging- increased autophagy can extend life in worms and other model organisms
8. Tumor suppression- e.g. an autophagy gene (Beclin 1) is a haploinsufficient tumor suppressor in mice.
9. Tumor promotion- e.g. required for progression and (perhaps) metastasis.
10. Inhibits apoptosis/ cell death but also kills cells. Type II programmed cell death.

Question 3

autophagy is

Answer 3

how stuff is delivered to lysosomes

Question 4

autophagy recycles proteins and other macromolecules under conditions of

Answer 4

under conditions of nutrient deprivation- allow recycling of amino acids, nucleotides and fatty acids.

Question 5

autophagy removes _____

Answer 5

organelles- mitochondria and peroxisomes.

and intra cellular pathogens

Question 6

autophagy allows cells to

Answer 6

survival under stress conditions (growth factor deprivation, hypoxia etc.)

Question 7

autophagy presents

Answer 7

Present antigens to MHC system

Question 8

autogphagy functions in neuro-protection: examples

Answer 8

e.g. remove protein aggregates to prevent neuronal damage in e.g. Huntington’s, Parkinson’s disease etc.

Question 9

autophagy and aging:

Answer 9

increased autophagy can extend life in worms and other model organisms

Question 10

autophagy and tumor suppression

Answer 10

e.g. an autophagy gene (Beclin 1) is a haploinsufficient tumor suppressor in mice.

Question 11

autophagy and tumor promotion

Answer 11

e.g. required for progression and (perhaps) metastasis.

Question 12

autophagy inhibits

Answer 12

apoptosis/ cell death but also kills cells. Type II programmed cell death.

Question 13

autophagy is induced during times of

Answer 13

nutrient stress

Question 14

Atg genes

Answer 14

regulate autophagy

Question 15

autophagic process

Answer 15

1. induction
2. vesiiclenucleation
3. vesicle expansion
4. cargo targeting
5. veiscle closure
6. vesicle fusion with endosome
7. vesicle fusions with lyosome

Question 16

induction

Answer 16

nutrient starvation, growth factor–mediated starvation exposure to chemo drugs, like rapamycin

Question 17

vesicle nucleation also called

Answer 17

phagophore

Question 18

vesicle expansion also called

Answer 18

also called omegasome

Question 19

examples of cargo targeting

Answer 19

LC3II and p62

Question 20

when vesicle closure occurs, it is called

Answer 20

autophagosome

Question 21

when the vesicle fuses with the endosome, called

Answer 21

amphisome

Question 22

when the vesicles fuses with the lysosome, it is then called

Answer 22

autolysosome

Question 23

What regulates autogphagy?

Answer 23

1. amino acids ad other nutrients
2. growth factors
3. lipids
4. everything that regulated the PI3 kinase pathway
5. Multiple protein kinases
6. tumor suppressor proteins like p53, positive and negative regulation
7. mutated oncogenes like Ras (positive and negative regulation

Question 24

Autophagy signaling often converges on the

Answer 24

mTOR pathway

Question 25

Beclin-1 interacts with Bcl-xL via

Answer 25

a BH3 domain

Question 26

The BH3 mimetic _____ and disrupts the ______

Answer 26

ABT 737

Beclin-1-Bcl-xl interaction

Question 27

Some examples of anti-cancer agents that have been proposed to work by inducing autophagic cell death

Answer 27

1. mTOR inhibitors
2. Topoisomerase inhibitors
3. Arsenic
4. Radiation
5. Vitamin D analogs
6. Oncolytic viruses
7. DNA alkylating agents
8. HDAC inhibitors
9. TRAIL

Question 28

______ inhibitors induced caspase-independent, autophagic cell death

Answer 28

HDAC

Question 29

knockout of autophagy can prevent

Answer 29

cell death

Question 30

autophagic cell death is associated with formation of

Answer 30

autophagic vesicles

Question 31

Autophagy is a

Answer 31

highly regulated process and likely important in many physiological and pathological processes.

Question 32

Autophagy is Intimately associated with

Answer 32

apoptosis & cell death

Question 33

autophagy can

Answer 33

kill cells or protect cells against nutrient deprivation induced stress, neurodegeneration and anti cancer agents

Question 34

Macroautophagy

Answer 34

• form a double membrane vesicle that captures cytosolic components/organelles. Then fuse with lysosome where hydrolases degrade contents of autophagosome.

Question 35

Chaperone-mediated–

Answer 35

recognition of specific proteins that contain a specific recognition sequence (based on amino acid sequence KFERQ). Direct binding and delivery to lysosome.

Question 36

Describe process of macroautophagy.

Answer 36

1. Activate a PI3K complex that allows nucleation of a membrane that will eventually form autophagosome.
2. Regulation of protein conjugation events to extend membrane.
3. Randomly capture, or specifically deliver cargo to the extending autophagosome, then join the membranes to close the vesicle.
4. Fuse with lysosome.
5. Recycle amino acids and other macromolecular precursors.

Question 37

Describe rationale behind autophagy’s protective action against neurodegeneration.

Answer 37

1. Aggregate-prone proteins (e.g. those with expanded stretches of glutamine residues in diseases like Huntington’s disease) will cause neuronal cell death.
2. Autophagy degrades the aggregate-prone proteins (perhaps after they have started to form small aggregates).
3. No toxic stimulus, no neuronal cell death.

Question 38

Identify mechanisms by which apoptosis induction and autophagy are connected.

Answer 38

Many proteins - e.g. Bcl-2 - that regulate apoptosis/ cell death, also control autophagy--remember, this could create problems in interpreting results of therapeutic interventions designed to target these proteins.  
Apoptotic proteases (caspases) can cleave essential autophagy regulators inactivating them and therefore blocking the process of autophagy.  
In some cases, -e.g. with starvation-induced cell death, it is easy to see why autophagy would protect– it provides essential nutrients at least in the short term.  
In others, e.g. stress-induced cell death from chemotherapy etc. its less clear why autophagy would be protective.

Question 39

Many proteins - e.g. _____ - that regulate apoptosis/ cell death, also control __________

Answer 39

Bcl-2

autophagy–remember, this could create problems in interpreting results of therapeutic interventions designed to target these proteins.

Question 40

Apoptotic proteases (caspases) can _______.

Answer 40

cleave essential autophagy regulators inactivating them and therefore blocking the process of autophagy

Question 41

In some cases, -e.g. with starvation-induced cell death, it is easy to see why autophagy would protect– _______

Answer 41

it provides essential nutrients at least in the short term.

In others, e.g. stress-induced cell death from chemotherapy etc. its less clear why autophagy would be protective.