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Biosci 353 > Module 1 > Flashcards

Module 1 Flashcards

1
Q

Where is autophagy tightly regulated?

A
  • Cell growth
  • Development
  • Disease
  • Homeostasis
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2
Q

Homeostasis

A

maintenance of equilibrium or stability within the cell in response to external pressures

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3
Q

Basic autophagy cycle

A
  • phagophore membrane expands around cargo
  • vesicle completed forming an autophagosome
  • autophagosome fuses with lysosome
  • cargo is degraded
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4
Q

What is a lysosome

A
  • membranous vesicle in animal cells that digests cellular material
  • terminal degradative compartment in endocytosis, phagocytosis and autophagocytosis
  • contains hydrolytic enzymes
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5
Q

What delivers contents to lysosome

A

endosome

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6
Q

Comparison of endosomes and lysosomes

A
  • lysosome come from golgi
  • endosome come from cell membrane
  • endosomes contain M6P receptor
  • both travel around cell via microtubular network
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7
Q

2 plausible theories of delivery to lysosomes from endosomes

A
  • kiss and run
  • hybrid model
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8
Q

What can lysosomes fuse with

A
  • endosomes
  • autophagosomes
  • phagosomes
  • plasma membrane
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9
Q

Components of a lysosome

A
  • LAMPs
  • Proton pump
  • ion channel
  • cholesterol transporter
  • sugar transporter
  • nucleoside transporter
  • amino acid transporter
  • SNAREs
  • tethering factors
  • GTPases
  • motor adaptors
  • signalling and transcription factors
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10
Q

Role of proton pump

A

maintains acidic pH inside lysosome for enzymes

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11
Q

Role of LAMPs

A

makes membrane robust and stable

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12
Q

Role of SNAREs and tethering factors

A

allows for membrane attachment

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13
Q

Role of motor adaptors

A

allows for movement

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14
Q

3 secretion and sorting pathways of proteins

A
  • signal mediated diversion to lysosomes
  • regulated secretion
  • constitutive secretion
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15
Q

Signal mediated diversion to lysosomes

A

proteins with M6P receptor are diverted to lysosomes via late endosomes

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16
Q

How the cell is protected throughout the lysosomal loading process

A
  • cytosol is not the pH for the enzymes to act
  • enzymes always contained within a vesicle
  • vesicles themselves are resistant to enzymes due to LAMPs
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17
Q

Macroautophagy

A

autophagosomes delivers contents to endosomes or lysosomes via fusion

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18
Q

Microautophagy

A

contents are directly engulfed by lysosomes via invagination or protrusions

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19
Q

Chaperone mediated autophagy

A
  • uses chaperones to identify cargo proteins which have a specific motif, these are then translocated into the lysosome
  • alternative to UPS
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20
Q

UPS process

A
  • ubiquitin activated via an E1 activating enzymes
  • ubiquitin transferred to target protein via E2 and E3
  • protein becomes poly-ubiquitinated and is degraded by the 26s proteasome
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21
Q

when does UPS fail

A

when proteins aggregate they then go to CMA

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22
Q

Baseline autophagy

A

randomly engulfs the contents within the area its in - IMPORTANT FOR HOUSEKEEPING

23
Q

Induced autophagy

A

selective and usually induced via starvation etc

24
Q

Membrane source from mitochondria

A
  • PS translocated from ER to mitochondria
  • PS to PE
  • PE attached to growing autophagosome membrane from mitochondria
  • LC3 attaches to PE = LC3-II
  • autophagosome expands and dissociates
25
Q

Membrane source from RER

A
  • cradle on RER buds off and forms autophagosomes
  • cradle forms from protein complexes at the surface inducing membrane curvature
26
Q

Membrane source from golgi

A

ATG 9 vesicles bud off from golgi providing lipids for autophagosome

27
Q

Possible membrane sources

A
  • ER
  • mitochondria
  • ER-mitochondria contact site
  • plasma membrane
  • golgi
  • ATG 9 vesicle
  • recycling endosomes
28
Q

Why is a double membrane important

A
  • proteins on inner membrane can recognise specific targets for selective autophagy
  • prevents leakage
29
Q

What is P62

A
  • an adaptor protein found on the inside of phagosomes
  • contain LIR and UBA domains allowing for LC3-II and cargo attachment at either end
30
Q

LC3 characteristics

A
  • has a lysine which allows for PE attachment through a ubiquitin like process
  • is ubiquitin like
31
Q

Why is LC3-II sometimes found on the outside of vesicles?

A

allows for attachment to kinesin so movement can occur

32
Q

UPR response

A
  • in response to cellular stress
  • halts protein translation
  • degrades misfolded proteins
  • activating signalling pathways for protein folding
  • restores normal function of ER
33
Q

ER autophagy Sec62

A
  • counteracts ER growth from UPR
  • conformational change in Sec62 translocation complex exposing its LIR domain
  • LIR becomes phosphorylated at the serine or threonine residues increasing it binding affinity for LC3-II
  • LC3-II binds and autophagosome forms engulfing ER material
34
Q

ER autophagy FAM134B

A
  • when ubiquitinated within RHD domain then a conformational change occurs causing clustering
  • clustering causes membrane curvature
  • has LIR domain allowing for LC3-II binding
35
Q

What affects transformation

A

environment - hypoxia, carcinogen etc

36
Q

Hypoxia produces cancer survival strategies via

A
  • increasing autophagy
  • survival in low nutrient microenvironments by adaptation
  • adapted cells are often more aggressive and resistant
37
Q

Reasons autophagy may suppress cancer

A
  • stress induces P62 = increased selective autophagy = removal of damaged proteins and organelles
  • prevents accumulation of genetic defects
  • prevents ROS production via removal of dysfunctional mitochondria
  • maintenance of normal stem cells
  • preserves genomic stability
  • oncogene degradation
  • anti inflammatory
38
Q

Reasons autophagy may promote cancer

A
  • delays apoptosis via providing nutrients for metabolism
  • promotes adaptation
  • allows survival of dormant cells
  • resistance to hypoxia and starvation
  • maintenance of cancer stem cells
39
Q

What are PROTACs

A
  • proteolysis targeting chimera
  • utilises UPS
40
Q

Components of PROTAC

A
  • POI ligand binding domain
  • E3 ligase binding domain
  • linker which has to be a specific length
41
Q

PROTAC E3 ligase considerations

A
  • shape complementarity
  • binding strength and affinity
  • subcellular localisation for region of degradation
  • cell type specific expression
42
Q

Advantages of PROTAC

A
  • has greater specificity than some kinase inhibitors
  • can be recycled so can be administered in low doses
  • can target proteins which are not normally targetable by inhibitors due to lack of active sites
43
Q

Disadvantages of PROTAC

A
  • possible toxicity
  • linker has to be correct = difficult
  • can only degrade intracellular, soluble and short lived proteins
44
Q

What are LYTACs

A
  • lysosome targeting chimera
  • utilises endosome-lysosome pathway
45
Q

Components of LYTACs

A
  • POI ligand binding domain
  • lysosome shuttling receptor binding domain (M6P)
  • flexible linker
46
Q

Possible problems with LYTAC

A
  • possible toxicity
  • immune responses
47
Q

What does LYTAC target

A

extracellular and membrane-bound proteins

48
Q

What can POI binding domains be made of

A
  • small molecule
  • antibody
  • peptide
49
Q

why does the linker length matter for PROTACs

A

need to have the correct length to specifically reach the lysine residue on the POI so it can be ubiquitinated

50
Q

What are the domains of autophagy adapter proteins?

A
  • LIR = LC3-II interaction region
  • UBA = ubiquitin recognition protein - recognises polyubiquitinated cargo
51
Q

Computational modelling of FAM134B

A
  • measured the time taken for vesicle completion
  • compared un-ubiquitinated vs ubiquitinated
  • Ubiquitinated had increased speed of vesicle completion - due to increased membrane curvature
52
Q

Liposome experiment FAM134B

A
  • Liposomes carried either GST-Ub, GST-RHD or GST-RHD-Ub
  • GST was a proxy protein and a protein purification tag
  • analysed and diameters were measured via TEM
  • GST-RHD-Ub had smallest diameter due to increased membrane curvature
53
Q

How does autophagy contribute to cellular renewal and survival

A
  • Cellular house keeping = quality control, constant membrane renewal
  • Cell survival during starvation, cell can use components released from degradation as nutrients
  • Renewal of membrane proteins
54
Q

Importance of ubiquitination process in autophagy

A
  • selective autophagy = polyubiquitin tag is recognised via adapter proteins such as p62
  • ER phagy = FAM134B, membrane curvature
  • LC3 = becomes lipidated by PE at lysine residue via ub like process

Biosci 353 (2 decks)

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