ASKEW

Question 1

The accumulation of unfolded proteins in the ER creates unfolded protein __________, activating a cellular stress response pathway called the __________.

Answer 1

stress, unfolded protein response (UPR)

Question 2

The entry point for most proteins destined for the cell surface or secretion is the __________. This organelle handles up to a __________ (fractional amount) of the cellular proteome.

Answer 2

ER, third

Question 3

Three mechanisms within the ER assist in the proper folding of proteins: __________, __________, and __________.

Answer 3

Chaperones, folding enzymes, N-linked glycosylation

Question 4

___________ associate with newly formed peptides, preventing improper interactions and stabilizing partially unfolded proteins.

Answer 4

Chaperones

Question 5

__________ catalyze the formation of disulfide bonds, frequently found in secreted proteins, while __________ accelerate the isomerization of proline peptide bonds, facilitating protein folding.

Answer 5

Protein disulfide isomerases; peptidyl prolyl isomerases

Question 6

In __________, a common oligosaccharide, synthesized on a lipid carrier in the ER membrane, is transferred to a growing polypeptide and subsequently trimmed in the __________ and __________ to aid in protein folding.

Answer 6

N-linked glycosylation; ER; Golgi

Question 7

The __________ is a 22 base pair DNA sequence found in the promoter region of genes involved in the unfolded protein response, and it was identified in __________.

Answer 7

UPRE (unfolded protein response element); 1992

Question 8

__________, a type I transmembrane protein with a kinase domain, was identified as the ER stress sensor in yeast using a genetic screen based on a __________.

Answer 8

Ire1; UPRE-reporter

Question 9

In yeast, the __________ transcription factor, encoded by a splice variant, plays a critical role in regulating the UPR.

Answer 9

Hac1

Question 10

Ire1 possesses an __________ domain in its cytosolic N-terminal region and is responsible for splicing the __________ mRNA to generate the active __________ mRNA, ultimately leading to the production of the functional Hac1 transcription factor.

Answer 10

RNAse-like; HAC1u; HAC1i

Question 11

The two models proposed for Ire1 activation are the __________ and the __________.

Answer 11

Direct binding model; chaperone inhibition model

Question 12

The mammalian UPR consists of three branches, including the conserved __________ pathway and two additional branches: __________ and __________.

Answer 12

IRE1; ATF6; PERK

Question 13

The __________ sensor is an ER transmembrane protein that, upon ER stress, translocates to the Golgi and undergoes cleavage by proteases, releasing its cytosolic transcription factor domain.

Answer 13

ATF6

Question 14

The __________ sensor, an ER transmembrane protein with a cytosolic eIF2α kinase domain, alleviates ER stress by phosphorylating __________, leading to global translational repression while simultaneously enabling the translation of specific transcription factors like __________.

Answer 14

PERK; eIF2α; ATF4

Question 15

__________, a process that eliminates terminally misfolded proteins from the ER through ubiquitination and proteasomal degradation, plays a crucial role in mitigating ER stress.

Answer 15

ERAD (ER-associated degradation)

Question 16

When the UPR fails to restore homeostasis, prolonged ER stress triggers the activation of __________, a key transcription factor involved in apoptosis.

Answer 16

CHOP

Question 17

Pharmacologic manipulation of UPR-mediated apoptotic pathways offers promising therapeutic strategies for treating __________ and __________.

Answer 17

Cancer; infections caused by intracellular microbes

Question 18

Inhibiting the UPR in __________ can induce toxic levels of unfolded proteins and trigger apoptosis, while suppressing UPR-mediated apoptosis in __________ may offer protection against cell loss associated with protein misfolding.

Answer 18

Cancer cells; neurodegenerative diseases

Question 19

The historical perspective of the UPR highlights how the field evolved from studying RNA tumor viruses, specifically __________, to investigating the protein __________, which was initially found to be induced by glucose starvation.

Answer 19

RSV (Rous sarcoma virus), GRP78 (glucose-regulated protein 78)

Question 20

GRP78 was later identified as __________, an ER chaperone known to interact with immunoglobulin heavy chains in B cells.

Answer 20

BiP (binding immunoglobulin protein)

Question 21

Scientists observed that __________, __________, and __________ all induce GRP78 expression, suggesting a common underlying mechanism related to protein folding stress in the ER.

Answer 21

Glucose starvation, glycosylation inhibitors, toxic amino acid analogues

Question 22

The yeast homolog of GRP78/BiP is called __________, and its gene, __________, was found to be induced by ER stress, paving the way for further investigation into the UPR in yeast.

Answer 22

Kar2p, KAR2

Question 23

Researchers utilized a yeast mutant, __________, that is temperature-sensitive for N-glycosylation to screen for mutants defective in UPR signaling, ultimately leading to the identification of the gene __________.

Answer 23

Sec53, Ire1

Question 24

The discovery that the intron in the __________ mRNA lacks consensus splicing sites and that Ire1’s RNAse domain is cytoplasmic suggested an unconventional splicing mechanism.

Answer 24

HAC1

Question 25

The crystal structure of Ire1, with its symmetrical dimer and a groove resembling the peptide-binding groove of __________, provided support for the direct binding model of Ire1 activation.

Answer 25

MHC (major histocompatibility complex) complexes

Question 26

___________, an ER chaperone, plays a key role in both the direct binding and chaperone inhibition models of Ire1 activation.

Answer 26

BiP

Question 27

The mammalian UPR exhibits two additional branches, absent in yeast, that contribute to relieving ER stress: the __________ sensor and the __________ sensor.

Answer 27

ATF6, PERK

Question 28

In the mammalian UPR, the __________ pathway is conserved and involves the splicing of the __________ mRNA to produce the active transcription factor that regulates the expression of UPR target genes.

Answer 28

IRE1, XBP1u

Question 29

The __________ is an adaptive stress response pathway activated by cells to cope with unfolded protein stress.

Answer 29

Unfolded protein response (UPR)

Question 30

The enzyme __________ catalyzes the formation of disulfide bonds between cysteine residues.

Answer 30

protein disulfide isomerase

Question 31

___________ is the enzyme that catalyzes the isomerization of proline peptide bonds.

Answer 31

Peptidyl prolyl isomerase

Question 32

The UPR involves signal transduction across the ER membrane to communicate ER stress to the __________.

Answer 32

nucleus

Question 33

Unfolded proteins can cause various problems for the cell, including __________, __________, __________, and __________.

Answer 33

Loss of function; proteome imbalance; illegitimate interactions; energetic cost of repair

Question 34

In mammalian cells, ___________ is a transcription factor activated by all three UPR pathways and is a key mediator of apoptosis in response to unresolved ER stress.

Answer 34

CHOP

Question 35

In the chaperone inhibition model, ___________ binding to Ire1 keeps the sensor monomeric and inactive.

Answer 35

BiP