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 when phosphorylated, and activates ATF4 (stress response gene).

ATF6

A UPR sensor protein that:

• translocates from the ER to the Golgi during ER stress

• 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 by splicing it so thatt it can trun on chaperones

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

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).

what are the 3 branches of UPR in multicellular eukaryotes

1. PERK

2. AT6F

3. IRE1

UPR 3 programs:

• Preemptive = slow down

  • Reduce protein synthesis/translation

• Adaptive = fix it

  • Produce more chaperones

  • ERAD removes misfolded

• Terminal = eliminate the cell

  • CHOP

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.

non-autonomous UPR responses: UPR affects metabolism & Bioactive Lipids

• UPR affects metabolism

  • influences circardian rythym & metabolic rythyms

  • coordinates how the whole organism responds to stress

• Bioactive Lipids

  • acts as a signaling molecule spreading through whole organism

non-autonomous UPR responses: 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 - cancer cells

Efflux pumps upregulated via IRE1 in cancer cells

• Pump chemotherapeutic drugs out of cells, contributing to treatment resistance.

blocking IRE1:

• prevent tumor regrowth

sensing ER homeostatic Deviations

• early models of UPR activation involved dissociation of Grp78

• IRE1 challenged this bc deleting Grp78 delays IRE1 activation and disrupts the ability to sense and respond to ER stress effectively.

context dependent UPR roles

cytoprotective —> protect cells

detrimental —> contributes to cell death

context dependent IRE1 & PERK

IRE1 deletion:

• accelerates age related cognitive decline (neurodegeneration)

increased IRE1:

• protect again alzheimers

PERK deletion:

• causes motor + cognitive impairment

PERK inhibtion:

• improve neurodegeneration in Parkisons