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MIMS > Cell Death > Flashcards

Cell Death Flashcards

1
Q

Cell death is the end of a response. True or false

A

No it is the beginning of an immune response

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2
Q

How many cells die a second

A

1 million

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3
Q

3 reasons cell death is used in normal physiology

A

Development/ ageing

Immune system

To protect from pathogens and tissue malfunction

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4
Q

What is modus operandi

A

Over production of excess cells in development to allow cell culling to select fittest cells and remodel

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5
Q

How many neurons dies in new born

A

60%

This is why identical twins aren’t completely identical - their neuronal network is different

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6
Q

Name a structure we are all born with but it only persists in females

What does it form

A

Mullerian duct

Uterus and oviducts

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7
Q

Name a structure we are all born with but it only persists in males

What does it form

A

Wolffian duct

Male reproductive organs

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8
Q

Why is cell death important in the immune system (3)

A

Many T lymphocytes are produced but only functional ones are selected
Those without a productive T cell receptor die by neglect

Faulty T cells that attack self are killed via negative selection

There is also T cell mediated murder (effector cytotoxic T cells initiate cell death in infected cells)
Also during an infection, T cells for that pathogen are in a very high number but after the infection this must decrease so cell death must occur

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9
Q

What is contraction

A

Reducing number of T cells after an infection is over

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10
Q

Cell death is important for homeostasis - Why

A

Balances with new cell production and well as relative fitness sensing

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11
Q

What happens if cell death exceeds new cell production (3)

A

Neurodegeneration

Immunodeficiency

Infertility

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12
Q

What happens if new cell production outweighs cell death

A

Cancer

Autoimmunity

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13
Q

What is relative fitness sensing and how does it relate to cell death

A

Every cell has a certain level of fitness which is cross referenced to the fitness standard of the organ.

If a cell is produced that is viable but doesn’t reach the fitness standard it is destroyed by the surrounding cells

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14
Q

Name a type of cell death that is immunologically silent and one that is immunogenic

A

Apoptosis = silent

Necroptosis = immunogenic

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15
Q

2 key aspects to consider about the cellular context of cell death

A

1) what was the cell death event

2) what were the underlying signalling events -> were inducible DAMPs produced?

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16
Q

What is a DAMP

A

Danger associated signalling event

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17
Q

4 reasons apoptosis is silent

A

The PM remains intact

Caspase dependant

Caspases incapacitate danger signals and ensure neat disposal of dead corpses

No DAMPs

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18
Q

What happens in all lytic cell deaths

A

Pore formation

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19
Q

Where aRe pores formed in a apoptosis

A

Mitochondrial membrane

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20
Q

What is the most common form of cell death

A

Apoptosis

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21
Q

Give the 5 morphological features of apoptosis

A 
Cell shrinkage
Membrane blebbing 
DNA fragmentation 
Apoptotic body formation 
Engulfment by neighbouring cells and phagocytes

MEMBRANE REMAIN INTACT

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22
Q

How long does engulfment take after apoptosis

A

15 mins

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23
Q

Give the structure of caspases

A

Homo dimers

Produced as inactive form and must be activated

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24
Q

Where do caspases cleave

A

After aspartate

Hence the name: cASPases

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25
Q

2 pathways to activate caspases

Give the key complex in each

A

Mitochondrial pathway - intrinsic - the apoptosome

Death receptor - extrinsic - DISC

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26
Q

What does DISC stand for

A

Death Inducing Signalling Complex

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27
Q

Which caspases do DISC and apoptosome activate

A

Apoptosome: 9
DISC: 8

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28
Q

2 groups of caspases

A

Initiator and executioner (these are subunits of initiator caspases)

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29
Q

Key differences between initiator and executioner caspases

A

Initiator:
•long pro-domain
• monomeric
• activated by dimerisation

Executioner
•obligate dimers
• activated by cleavage

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30
Q

3 features common to all caspases

A

Made of Pro enzymes
Active as dimers
Cys Asp proteases

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31
Q

3 targets for initiator caspases

A

Themselves
Effector caspases (Casp-3, and -7)
BCL-2 homology 3 (BH3) - BID

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32
Q

5 things effector caspases (eg Casp 3,6 and 7) do

A
  • Dismantle cell structures
  • Phenotypic changes to cell that are characteristic of apoptosis
  • cleavage of ICAD, which releases CAD
  • proteolysis at adhesion sites allowing cell detachment and retraction
  • exposure of PS and other phagocytic signals on the cell surface
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33
Q

What does CAD do in cell death

A

Cut up the DNA

CAD = Caspase activates DNA-ase

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34
Q

How are initiator caspases activated

A

Proximity induced dimerisation
- certain ligands change the configuration of a death ligand, allowing recruitment of adapter protein with a death domain

The death domain brings in 2 Casp 8 molecules which dimerise and activate

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35
Q

What does cytochrome c do after it is released from the mitochondria

A

Binds to an Apaf-1 molecule which binds to other Apaf-1 molecules forming an apoptosome

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36
Q

How is Casp 9 activated

A

It sits on top of the apoptosome and dimerises

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37
Q

Why are executioner caspases activates by cleavage

A

The catalytic cysteine is masked and cleavage unmasks it allowing substrate entry

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38
Q

Is cell death assured once caspases are activated

A

No IAPs (inhibitor of apoptosis proteins) can inhibit caspases

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39
Q

Where were IAPs discovered

A

In viruses

40
Q

What is the point of no return in apoptosis

A

MOMP

41
Q

What is the anti apoptotic family that inhibits Bak (pore forming proteins)

A

The BCL-2 family

42
Q

What do bak and bax proteins do

A

Form pores in the mitochondria

43
Q

What do BH3-only family members do

A

Suppress BCL-2 family, allowing Bax and thus pore formation in the mitochondria leading to apoptosis

44
Q

How many proteins in a cell can be cleaved by caspases

A

2000

45
Q

How do extrinsic signals initiate cell death

A

The death ligand binds to the death receptor, causing it to trimerise

46
Q

What happens after the death domain trimerises when the death ligand binds

A

FADD (an adapter protein) is recruited which in turn brings casp 8 molecules to be activated

47
Q

How does FADD from the death receptor activate casp 8

A

There is a proximity induced conformational change that rotates the catalytic centre into an active position

48
Q

What are the 2 different forms of extrinsic induced apoptosis

A

Type I: activated casp 8 activates casp 3 and 7, directly leading to apoptosis (no MOMP required)

Type II: casp 8 cleaves BID, which activates Bak and MOMP for pore formation in the mitochondria

49
Q

What happens to XIAP in Type I and Type II cells in apoptosis

What XIAP do

A

Type I: XIAP rapidly decreases upon activation of death receptor

Type II: SMAC is released from mitochondria after pore formation and inhibits XIAP

XIAP inhibits apoptosomes and casp 3 and 7, ultimately inhibiting apoptosis

50
Q

What is special about the TNF death receptor

A

It can send 2 different signals: one for cell survival (the dominant outcome) and one for cell death

51
Q

What molecule is activated by a TNF death receptor to initiate cell death

When is this released

A

RIPK1

If the cell is not fit enough / under stress as TNF tests cells for fitness

52
Q

What do TRADD and RIPK1 recruit

What is important about these

A

TRAF1, cIAP, LUBAC

They recruit ubiquitin chains - different chains either determine cell death or gene expression

53
Q

If RIPK1 recruits a ubiquitin chain NOT for cell death, what recognises the ubiquitin chain

What about for TRADD

What does this eventually lead to

A

TAB2

NEMO

Activation of NF-κB

54
Q

What is the ubiquitin checkpoint

A

If RIPK1 and TRADD, bound the the TNF death receptor, have a ubiquitin chain not signalling cell death, the complex remains attached the the plasma membrane

If the ubiquitin chain signals cell death, the RIPK1 is released and RIPK1 oligomerises and binds to FADD, allowing casp 8 to be activated by proximity. This leads to apoptosis

55
Q

When RIPK1 oligomerises and activates Casp 8, what is this complex called

If this is formed, is cell death certain

A

Complex 2

No - cFLIP can mediate complex 2 activity

56
Q

What is FLIP

A

A pseudo caspase

Like a caspase in structure but with a mutated catalytic centre
It can dimerise with casp 8

57
Q

What does FLIP do

A

Dimerises and tethers casp 8 so it cannot cleave you activate effector caspases

58
Q

What can The dimer of FLIP + casp 8

A

Cleave RIPK1 and RIPK3 to disable them and allowing survival

59
Q

Does the RIPK1 complex 2 always lead to apoptosis

A

No it can activate MLKL pathway for necropotosis

60
Q

When virus prevent cell death what do they target

A

The extrinsic apoptosis pathway, often targeting caspases

61
Q

Which viral proteins attack casp 8

A

CrmA and vFLIP

62
Q

Which viral proteins attack executioner proteins

A

vIAP

63
Q

When does necroptosis occur

A

When caspases like casp 8 are blocked

64
Q

Does necroptosis affect the mitochondria

A

No it makes holes in the PM instead

65
Q

What is the main trigger of necroptosis

A

Pathogens

Cell stress damage

66
Q

What are the 2 domains of RIPK1

A

Death domain and kinase domain

67
Q

What is a ripoptosome

What inhibits it

A

The RIPK-FADD complex that can activate either casp 8 or MLKL as well as NF-κΒ for danger signals

cIAP1 and 2
XIAP

68
Q

How does MLKL work

A

It is a pseudo kinase that is activated via phosphorylation by the ripoptosome

69
Q

How does phosphorylation activate MLKL

A

A 4HB disengages, exposing the domain allowing dimerisation and thus pore formation

70
Q

Other than TNF what can initiate necroptosis (3)

A

When ZBP1 senses a virus and uses its RHIM domains to bind and activate RIPK3

IFNs initiate necroptosis when FADD is absent

LPS binds TLR4 to initiate necroptosis via TRIF

71
Q

What are the 3 outcomes of a death receptor pathway

A

Survival
Apoptosis
Necroptosis

72
Q

What is RHIM

A

RIP homology interact motifs

They allow RIPK1 and RIPK3 to interact

73
Q

Give the sequence of events of necroptosis starting with RIPK1 and RIPK3 interaction

A

RIPK1 and 3 interact through their RHIMs

Activated RIPK3 phosphorylates MLKL

MLKL undergoes conformational change to allow oligomerisation and then pore formation in PM

74
Q

How does RIPK1 interact with Casp 8

A

Casp 8 is cleaved and Inactivated

75
Q

Do carnivores have MLKL

Why?

A

No

Pathogens have won the race?

76
Q

Is pyroptosis caspase dependant

A

Yes- it mainly uses casp 1 and 11

77
Q

How does pyroptosis blow up the cell

A

Gasdermin- D forms pores in the PM and water comes in to swell the cell

78
Q

What does casp 1 activate in pyroptosis

A

IL-1β and IL-18

It also cleaves DNA so other casp can become active

79
Q

What are always the final 3 steps leading to pyroptosis

What is different

A

ASC activates casp 1 which activates IL-1β and IL-18

Different stresses have different triggers and sensors

80
Q

How is casp 1 activated

A

NLRP3 oligomises to form an inflammasome and ASC forms filaments which recruit and activate casp 1

81
Q

What is PAMP vs DAMP

A

PAMP is a pathogen induces danger signal where as DAMP is endogenous

82
Q

What is the back up system for pyroptosis

When is it needed

A

Inflammasome instead drives activation of casp 8

If casp 1 is deactivated

83
Q

What happens if NKRP3 is spontaneously activated

A

Chronic inflammation etc

84
Q

Give 3 initiator caspases

A

2
8
9

85
Q

Give 3 executioner caspases

A

3
6
7

86
Q

What does TNF do

A

Tests the fitness of cells

87
Q

How does casp 8 block necroptosis

What happens if casp 8 is low? When can this also happen?

A

By cleaving RIPK1 and RIPK3

RIPK1 activates RIPK3 which in turn activates MLKL. This will also happen if IAP is low

88
Q

What is the key effector of necroptosis

A

MLKL

89
Q

In which form of cell death is nuclear integrity maintained

A

Pyroptosis

90
Q

How are initiator caspases activated?

Why

A

Dimerisation

Can only be properly activated when there are enough present

91
Q

Key casp for pyroptosis

A

Casp 1

92
Q

What activates casp 1

What do interleukins do

A

Inflammasome

Create Gasdermin D pores

93
Q

Which cell death modality uses lipid peroxidation?

A

Ferroptosis

94
Q

What is SMAC / DIABLO

A

Inhibitors of apoptosis

95
Q

What is BH3 present in

A

BCL-2 (anti apoptotic)

But also BID (pro apoptotic)

96
Q

Describe the domains of the Bcl2 family

A

All anti apoptotic members have all BH domains (1-4)

All pro apoptotic have at least BH3 (BID has only BH3, Bak has several BH domains)

MIMS (12 decks)

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