Unfolded Protein Response (UPR)

Vocabulary flashcards generated from lecture notes on the Unfolded Protein Response (UPR), covering signaling branches, UPR programs, cell-nonautonomous signaling, and disease contexts.

Unfolded Protein Response (UPR)

A stress-sensing and signaling network in eukaryotic cells that maintains homeostasis by rebalancing the endoplasmic reticulum's (ER) biosynthetic capacity according to need.

ER Stress

A cellular condition triggered by misfolded or unfolded protein accumulation, changes in membrane lipid composition, or calcium imbalances in the endoplasmic reticulum.

UPR Dynamic Signalling

The mechanism where ER stress signal intensity, frequency, and duration are encoded to dynamically tune cellular outcomes between homeostasis adaptation and cell death.

GRP78 / BiP

An ER lumenal chaperone and UPR regulator that binds to exposed hydrophobic regions of unfolded proteins.

PERK

A UPR sensor protein that oligomerizes during ER stress, phosphorylates $eIF2\alpha$ to decrease global protein translation, and activates ATF4.

ATF6

A UPR sensor protein that translocates from the ER to the Golgi apparatus during ER stress, where it undergoes proteolysis to produce active ATF6(N) to increase ER chaperones.

IRE1

A UPR sensor protein that oligomerizes during ER stress and activates $XBP1$ mRNA splicing to produce the functional transcription factor XBP1s.

eIF2$\alpha$

A translation initiation factor that, when phosphorylated downstream of PERK, decreases cell-wide protein translation to reduce protein entry into the ER.

ATF4

A transcription factor selectively translated following $eIF2\alpha$ phosphorylation that promotes the activation of stress response genes.

CHOP

A transcription factor downstream of terminal UPR signaling that promotes apoptosis during severe stress by decreasing anti-apoptotic Bcl-2 and increasing pro-apoptotic DR5.

ERAD

Endoplasmic Reticulum-Associated Degradation; cellular machinery activated during the UPR to remove and degrade misfolded proteins from the ER.

Ire1 and Hac1

The single major sensor (Ire1) and single effector (Hac1) that comprise the simple UPR pathway in unicellular eukaryotes like yeast.

Lipid Bilayer Stress

ER membrane imbalances detected by UPR sensors, caused by changes in saturated phospholipids, sterols, membrane thickness/fluidity (activating IRE1 and PERK), or sphingolipids (activating ATF6).

Preemptive UPR Program

An immediate early response to ER stress involving IRE1 and PERK that acts to slow down protein synthesis and translation to reduce ER load.

Adaptive UPR Program

A UPR gene expression program driven by XBP1s, ATF6N, and ATF4 that increases ER chaperones, foldases, and ERAD to expand ER processing capacity.

Terminal UPR Program

A UPR outcome occurring when ER stress is severe and unresolvable, wherein IRE1 signaling abates and PERK-CHOP signaling drives cell-autonomous apoptosis.

Cell-Nonautonomous UPR

A system where UPR signaling in one cell or tissue extends beyond the stressed cell to communicate signals that affect distant cells or tissues.

Glial XBP1 Signaling

A cell-nonautonomous UPR pathway in glia that causes adaptive changes in non-XBP1-expressing target cells and can extend lifespan in C. elegans.

Amyloid-$\beta$ and Tau

Misfolded protein aggregates associated with ER stress and UPR activation in Alzheimer's disease.

$\alpha$-Synuclein

Misfolded protein aggregate associated with ER stress and UPR activation in Parkinson's disease.

Polyglutamine

Misfolded protein repeat associated with ER stress and UPR activation in Huntington's disease.

ABC Transporters in UPR

Efflux pumps upregulated via IRE1 in cancer cells that pump chemotherapeutic drugs out of cells, contributing to treatment resistance.