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CELL 301 > Section 3 - Interorganeller Stress > Flashcards

Section 3 - Interorganeller Stress Flashcards

1
Q

Heat-shock proteins (HSPs) (def.)

A

constitutively expressed molecular chaperones that guide the normal folding, intracellular disposition and proteolytic turnover of many of the key regulators of cell growth and survival

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2
Q

HSP expression increase in response to ?

A

-heat/temperature change
-inflammation
-other protein-denaturing stressors

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3
Q

HSP expression increases in response to protein denaturing stressors as an _____

A

evolutionary conserved response to restore normal protein-folding environment and enhance cell survival

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4
Q

in tissues exposed to heat, proteins are ____

A

unfolded and aggregrate

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5
Q

source of heat in the cell

A

mitochondria, peroxisomes

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6
Q

HSP are mostly ____ and they help _____

A

-chaperones
-newly synthesized proteins fold

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7
Q

HSP protect proteins from ______

A

cellular stresses that can cause unfolding and aggregation

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8
Q

HSP target proteins to ______, prevent and clean up ______

A

-degradation
-protein aggregates

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9
Q

______ are a hallmark of neurodegenerative diseases

A

protein aggregates

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10
Q

proteins are folded to reach ____

A

energy minimum

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11
Q

large proteins require ___ to reach energy minimum

A

energy inputs

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12
Q

as protein chain forms more intrachain contacts, it lowers its _____ (2)

A

-internal free energy & reduces conformational freedom

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13
Q

heat shock is lethal to cells injected with ____

A

antibodies against Hsp70

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14
Q

generation of antiserum/antibody

A

1) transformation of bacteria with cDNA
2) produce proteins
3) inject proteins into mouse to make antibodies

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15
Q

Hsp70 requires binding and hydrolysis of ____ to ____

A

-ATP
-achieve folding

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16
Q

protein binding to Hsp70 occurs when _____, a state promoted by _____. release requires _____

A

-ADP-bound
-J-proteins (they remove P from ATP)
-ATP hydrolysis

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17
Q

ER equivalent of HSP70

A

GRP78/BiP

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18
Q

Ulk1 (part of _____) interacts with ____ but not its _____

A

-autophagy
- Hsp90 (and Cdc37)
- kinase-dead mutant form

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19
Q

inhibitor of Hsp90

A

geldanamycin + variant: 17AAG

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20
Q

The inhibition of Hsp90 with the geldanamycin variant 17AAG does what?

A

degrades Ulk1

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21
Q

The effect of Hsp90 inhibition on autophagy

A

-can’t trigger autophagy

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22
Q

effect of Hsp90 degradation on mitography

A

Hsp90 degradation blocks CCCP-mediated mitophagy

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23
Q

Hsp90/Cdc37 and Ulk1 kinase activity are needed to _____

A

undergo mitophagy

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24
Q

Heat shock proteins in cell

A

Hsp70
Hsp90

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25
Q

Hsp70 job in cell

A

-anti-aggregation
-membrane translocation
-intracellular disposition

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26
Q

Hsp90 job in cell

A

ligand binding, phosphorylation, dimerization

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27
Q

Overview of protein folding in the ER

A

-protein translocated into ER through Sec61 complex
-BiP/GRP78 (ER-localized Hsp70) binds to translocated protein in ATP-dependent manner
-co-translational folding follows glycosylation
-calnexin binds to glycosylated proteins to promote proper disulfide bond
-disulfide bond formation is mediated by PDI,ERp57

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28
Q

oxidation of proteins in ER forms _____ using ____

A

-disulfide bonds
-PDI in oxidized form

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29
Q

Ero1 does what?

A

oxidizes PDI (reduced to oxidized form) in ER, uses O2
-Ero1 goes from oxidized to reduced

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30
Q

ROS production in ER occurs when _____

A

substrates or enzymes involved in protein folding (ex. PDI, Ero1) are not present in correct amounts

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31
Q

Em405/Em440 ratio in ER indicates _____. The ___, the better

A

-oxidizing environment of ER
-higher

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32
Q

SERCA is what? function

A

-sarco/endoplasmic reticulum Ca2+-ATPase
-transport calcium from the cytosol into the sarcoplasmic reticulum

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33
Q

Calcium depletion via SERCA inhibition with this drug (______) leads to the _____. Hence this inhibits ______.

A

-TG=thapsigargin
-reduction of the ER lumen, but not of the cytosol
-pro-oxidants within the ER

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34
Q

ATP depletion by ____ inhibits ___ activity

A

-hypoxia, cut off glucose supply
-BIP

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35
Q

Block of glycosylation by _____ inhibits ___ activity

A

-tunicamycin
-Calnexin

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36
Q

Reduced calcium content by _____ inhibits ___ activity

A

-thapsigargin
-Calnexin, PDI

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37
Q

Reduction of the ER environment by ____ inhibits ___ activity

A

-DTT
-PDI

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38
Q

sequence conserved in BiP/GRP78/94 of mamalian and yeast promoters that is import for the induction by unfolded proteins in ER

A

unfolded protein-response element

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39
Q

when ER is stressed, BiP does what? then what happens?

A

-dissociates from ER folding sensors
-unfolded protein response occurs

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40
Q

UPR (_____) uses three ER sensor proteins to do what?

A

-unfolded protein response
-signal to nucleus

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41
Q

Three ER sensor proteins involved in URE + function

A

-IRE1 (induction of chaperones)
-PERK (translation inhibition)
-ATF6 (induction of chaperones, CHOP)

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42
Q

ER sensor proteins are regulated by ______. Loss of BiP binding causes _____

A

-BiP binding
-dimerization (IRE1, PERK) or ER-Golgi migration (ATF6)

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43
Q

Upon activation, IRE1 becomes _____, PERK exposes a _____ and ATF6 migrates to the _____

A

-an endonuclease (for XBP1)
-cytosolic kinase domain (for eIF2a)
-Golgi, where a cytosolic transcription factor domain is released

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44
Q

XBP1 transcription is induced by _____ and spliced by ____ in response to ____ to produce _____

A

-ATF6
-IRE1
-ER stress
-highly active transcription factor

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45
Q

The XBP-1 protein is only expressed at its full-length size (bigger) under ______.

A

-ER stress conditions

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46
Q

The XBP-1 splicing mechanism

A

Excision of 26bp allows translation of the 50 kDa XBP-1 protein that is (among other things) required for B cell development; yeast Hac1 splicing highly similar

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47
Q

Ire1p makes_____ during ER stress, to which the _____

A

-foci
-mRNA of XBP1 attaches

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48
Q

PERK can do what?

A

phosphorylate eIF2α, the eukaryotic translation initiation factor 2 subunit 1 (eIF2α), but also autophosphorylate

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49
Q

in vitro assay, PERK activity leads to _____

A

protein synthesis shutdown

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50
Q

Kinase dead PERK can’t do what?

A

shutdown protein synthesis

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51
Q

PERK autophosphorylation is tied to _____

A

-ER stress

52
Q

translocon component ___ acts in ER turnover during ____

A

-Sec62
-stress recovery

53
Q

Depletion of Ca2+ from the ER through treatment with _____ induces _____. Following removal of the stress, _____

A

-cyclopiazonic acid (inhibits ER filling)
-UPR-associated ER chaperones
-ER homeostasis is re-established

54
Q

BafA1: bafilomycin A1 blocks _____

A

lysosome/autophagosome acidification and hence cathepsins (proteases)

55
Q

Herp is what?

A

an ER membrane protein upregulated by ER stress, is implicated in regulation of ERAD

56
Q

Calnexin action during ER stress recovery

A

forms clusters within puncta (clumps)

57
Q

Calnexin clustering requires ____

A

Sec62 portion of translocon

58
Q

Sec62 interacts with ____ during ER stress recovery

A

LC3 (autophagy)

59
Q

Condition of cell that activates PERK

A

hypoxia

60
Q

the mitochondria and the ER make _____ that mediates _____

A

-extensive contacts
-calcium signalling

61
Q

lesser known partner of GFP

A

aequorin

62
Q

Histamine-triggered opening of IP3Rs demonstrates that ______

A

mitochondria must lie close to the mouth of ER Ca2+ release

63
Q

IP3R is what?

A

calcium channel; allows for release of Ca++ from ER into mitochondria

64
Q

calcium shuttling between ER and mitochondria

A

-3uM ATP or IP3 (release through IP3R) causes release of Ca++ from ER
-calcium uptake by mitochondria
-calcium uptake by serca in ER
(cycle repeats)

65
Q

Mitochondria-associated membranes (MAM) represent a ________

A

region of the endoplasmic reticulum (ER) which is reversibly tethered to mitochondria

66
Q

SERCA calcium pump and IP3R form a ______

A

calcium shuttle platform between the ER and mitochondria at the MAM

67
Q

ER-mitochondria calcium cycle is required for ____ in mitochondria

A

-the Krebs cycle

68
Q

conc of calcium in mitochondria compared to ER

A

ER: higher
mitochondria: lower

69
Q

Mitochondria calcium uptake increases during _____

A

exercise

70
Q

MCU (_______) -mediated calcium flux is necessary for _____

A

-mitochondrial calcium uniporter
-peak muscle performance during exercise

71
Q

Calcium release from the ER is essential for normal mitochondrial respiration, as seen by ______

A

reduction of respiration in full IP3R KO

72
Q

Energy crisis from mitochondrial Ca2+ deficiency activates ____

A

autophagy

73
Q

inhibitor of IP3Rs

A

XeB (xestospongin B)

74
Q

XeB effect on cancer cells

A

-causes energy crisis which activates AMPK but only kills malignant cancer cells

75
Q

The connection between the ER and mitochondria becomes tighter after ______, showing role for ____

A

-24h of ER stress
-protein folding and apoptosis

76
Q

evidence of lipid shuttling between organelles: PS synthase (makes phospatidylserine) is found in _____. PS decarboxylase (makes ______) localizes to ____

A

-MAM
-PE
-mitochondria

77
Q

Multiple contacts exist between _____. Many of their functions include _____, similar to what happens between the ER and mitochondria.

A
  • virtually all organelles
  • lipid and calcium homeostasis
78
Q

interactome (def.)

A

-is the whole set of molecular interactions in a particular cell, almost like one big organelle

79
Q

Lipid synthesis takes place mostly at which organelle?; the bulk of their synthesis has been localized to the _____

A

-the ER
-mitochondria-associated membrane (MAM)

80
Q

Lipid bodies are considered _____ that have a distinct ______. They can be generated in _____ with high concentrations of ______

A

-organelles
-set of proteins involved in their biogenesis and regulation
-all cell types so far
- fatty acids

81
Q

lipid bodies usually store ____ but in some cell types they have ____

A

-fatty acids
-specialized functions

82
Q

lipid bodies specialized function in liver cells

A

storage of vitamin A precursor

83
Q

lipid bodies specialized function in eyes

A

-storage of precursor for rhodopsin (needed for retinal pigment)

84
Q

lipid bodies specialized function in mammary epithelial cells

A

production and secretion of milk fat globules

85
Q

lipid bodies specialized function in eosinophils

A

storage of arachidonic acid

86
Q

adipocytes lipid droplets are rich in _____ while other cells usually contain _____

A

-cholesterol
-next to none

87
Q

lipid droplet creation

A

1) neutral lipids are synthesized between the leaflets of ER membrane
2) Mature lipid droplet then bud from ER membrane to form an independent organelle coated by monolayer of phospholipids and members of PAT-domain family of proteins

88
Q

PAT-domain family of proteins

A

perilipin, ADRP and TIP47-related protein-domain family of proteins

89
Q

lipid bodies originate from ____

A

ER

90
Q

The association of PAT proteins (______) with lipid bodies is _______ coordinated

A

-perilipin, adipophilin, TIP47
-spatially and temporally

91
Q

Lipid bodies remain associated with the_____ to facilitate _____. They can also be found associated with other organelles such as ______.

A

-ER membranes and mitochondria
-lipid exchange
-endosomes

92
Q

proteins involved in lipid trafficking

A

ORP5 and ORP8

93
Q

ER transmembrane proteins ________ both contain ____ domains that specifically interact with _____ and ORD domain which is the ______

A

-ORP5 and ORP8
-PH
- PI4P/phosphatidylserine
- lipid binding domain

94
Q

TIRF (_____) allows to observe _____

A

-total internal reflection fluorescence
-less than 200nm thick slices on the surface of cells

95
Q

co-expression of PI4K and ORP5 leads to ____

A

higher amounts of PI4P on PM and more ORP5 near the PM

96
Q

the double knockdown of ORP5/6 results in PS _____

A

no longer at PM

97
Q

PI4P used as signal at ER-PM contacts to establish ______. Machinery depends on the lipid transfer proteins _____

A

-PS enrichment on the inner leaflet
-ORP5 and ORP6

98
Q

PI-3P (_____) functions as signal for ______

A

-Phosphatidylinositol 3-phosphate
-membrane bending (e.g. autophagosome)

99
Q

PIP and PIP2 can be further phosphorylated to give _____

A

-3-phosphorylated phosphatidylinositol by the PI-3 kinase enzymes.

100
Q

The 3-phosphorylated phosphatidylinositol serves as a _____

A

-scaffold for the activity of the kinase Akt/PKB

101
Q

PI-3P acts a signal to block _____

A

-apoptosis via Akt and Bcl2 family protein Bad

102
Q

Trophic factor binding leads to activation of____ through _____. This then causes sequestration of _____. This prevents _____

A

-Akt
-PI-3 kinase
-Bad with 14-3-3 protein after Bad phosphorylation
-cell death

103
Q

PTEN (______)is found frequently ____ in tumours

A

-tumor suppressor gene
-mutated

104
Q

PTEN function

A

phosphatase (dephosphorylate PIP3 to make PIP2 which results in inhibition of the Akt signaling pathway, which plays an important role in regulating cellular behaviors such as cell growth, survival, and migration)

105
Q

Plentiful energy stops apoptosis, autophagy and promotes protein synthesis with ____

A

two mTOR complexes sitting at the central control point.

106
Q

mTOR stands for _____

A

mammalian target of rapamycin

107
Q

rapamycin does what?

A

inhibits mTOR; immunosuppressant(used for people who have organ transplants); anti-proliferative drug

108
Q

mTOR undergoes activation upon ____ and inactivation upon _____. Inhibition of mTORC1 stops _____. mTORC2 is most important for ______.

A

-hyperactive PI3K (cancer)
-an energy crisis (blocked respiration or glycolysis that makes AMP/ATP unfavorable and activates AMPK)
-cancer growth
-cell structure

109
Q

mTOR activates signal transduction pathways leading to the activation of _____

A

T helper cells

110
Q

_____ is one protein required for rapamycin toxicity in yeast. Without it, cell will do what in the presence of rapamycin?

A

-FKBP
-survive

111
Q

TOR2 (mTOR in ___) is what?

A

-yeast
-essential phosphatidyinositol linase homolog needed for G1 progression

112
Q

TOR controls ____

A

translation initiation and early G1 progression

113
Q

TOR2 is required for organization of _____

A

actin cytoskeleton, preventing growth

114
Q

_____ is a prerequisite for growth

A

-Normal cytoskeleton

115
Q

TCP20 is what?

A

an actin chaperonin

116
Q

cell with TOR2 deleted has _____; phenotype is rescued by _____

A

-aberrant actin cytoskeleton,; random actin dots
-TCP20

117
Q

T17N mutants = ______

Q61L mutants = ______

A

-permanently bound to GDP, also called kinase-dead
-permanently bound to GTP, also called dominant active

118
Q

TOR2 activates _____ via GEF _____ which makes them ____

A

-RHO1, RHO2
-ROM2
-GTP-bound/active

119
Q

active RHO1/RHO2 do what?

A

remodel actin cytoskeleton

120
Q

active RHO1/2 is inactivated by _____

A

Sac7p (Rho GAP)

121
Q

Tor2p absence can be rescued by _____

A

Rho1p or Rho2p

122
Q

Rapamycin acts by forming a _____

A

toxic complex with its intracellular receptor FKBP12, and this complex then binds and inhibits TOR directly

123
Q

in cells, there are two TOR complexes (______) and ____

A

-TORC1 (has TOR1/2) and TORC2 (has only TOR2)
-only one is rapamycin sensitive

124
Q

TORC2 controls ____ and is rapamycin ______

A

-actin cytoskeleton
-insensitive

125
Q

In S. cerevisiae, FKBP12 is encoded by the ____, and FPR1-rapamycin specifically binds and thereby inhibits ____

A

-FPR1 gene
-TOR1 and TOR2, but not the TOR2-based TORC2 complex

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