L23/24 - Autophagy and apoptosis

Question 1

define autophagy

Answer 1

proscess to degrade and reccyle ctoplasmic contnets via lysosomal pathway

3 main forms:
- macroauto
- microauto
- chaperone-mediated

Question 2

describe the 3 different forms of autophagy - macroautophagy,microautophagy and chaperone-mediated

Answer 2

macro:
forms double-membrane autophagosome that engulfs organelles or protein aggregates
- autophagosome fuse with lysosome = contents degraded

= regulated by mTOR (inhibitor) and AMPK (activator)

Micro:
direct engulfment of cytosolic componet via ‘invagination’ of lysosomal membrane

= less slective = bulk degredation

Chaperone-mediated:
selectiev degredation of specifc proteins with KFERq-like motif

= recognised by Hsc70 chaperons –> tarnsported to lysosomes by LAMP-2A receptors

Question 3

describe the steps in macroautophagy

Answer 3

1. mTORC1 inhibition + AMPK activation triggers ULK1 activation -> phagopore formation
2. class-3-PI3K complex generates lipid (PI3P) membrane and recruits proteins for expansion
3. membrane expansion and cargo recruitment
4. mature autophagosome fuses with lysosome –> autolysosome

= cargo degraded and recycled

Question 4

promoter and suppressor roles of autophagy in cancer

Answer 4

tumour suppressor:
prevent accumulation of damaged organelles and ROS

tumour promoter:
helps cancer survive in nutrinet-poor environment + resist therapy

Question 5

how do autophagy and apoptosis link together

Answer 5

both activated by cellular stress

Beclin-1 in both pathways:
1. Beclin-1 (autophagy protein) binds Bcl-2 (anti-apoptic)
2. caspases cleave Beclin-1 –> autophagy inactivated -> promotes apoptosis

Question 6

describe the intrinsic (mitochondrial) model for apoptosis

Answer 6

triggered bu DNA damage/stress

= cytochrome C released from mitochondria
= apoptosome forms –> Apf1 + Caspase-9

activates Caspase-3 (excecutioner caspase)

Question 7

describe the extrinsic (death receptor) apoptosis model

Answer 7

1. external ligand binds like FasL bind to death receptor
2. activate caspase-8 –> downstream caspase activation

Question 8

describe Necroptosis -new non-apoptic BUT regulated form of cell death

Answer 8

triggered when apoptosis is blocked –> casapse inhibitors

= membrane rupture
= linked to viral infection,stroke and cancer

Question 9

describe pryoptosis -new non-apoptic BUT regulated form of cell death

Answer 9

inflammatory death in immune cells

triggered by inflammasomes in response to pathogens

1. Caspase-1 cleaves gasdermin D = forms pores in membrane
2. release IL-1β + IL-18 = triggers immune response

Question 10

describe Ferroptosis -new non-apoptic BUT regulated form of cell death

Answer 10

iron dependent

iron overload –> ROS overload

target for anti-cancer drugs to trigger death in therapy-resistant cells