Endoplasmic reticulum stress & the unfolded protein response (UPR)

When folding demand exceeds ER capacity—nutrient stress, calcium dyshomeostasis, or glycosylation defects—misfolded proteins accumulate and trigger the UPR. PERK–eIF2α–ATF4, IRE1α–XBP1, and ATF6 arms sense load and reprogram translation, ERAD, and transcription to restore proteostasis; chronic hyperactivation couples to CHOP-driven apoptosis, autophagy, and inflammation.

1. Key targets

UPR sensors & branches

  • PERK / EIF2AK3

    Transmembrane kinase; phosphorylates eIF2α to attenuate global translation while favoring ATF4.

  • IRE1α / ERN1

    Kinase/RNase; splices XBP1 to XBP1s; RIDD degrades select ER-localized mRNAs.

  • ATF6

    Golgi proteolysis releases an active fragment upregulating chaperones and ERAD components.

Chaperones & folding QC

  • BiP / GRP78（HSPA5）；Calnexin / Calreticulin 糖蛋白折叠周期
  • PDI family, ERdj co-chaperones, ERAD (e.g., SEL1L–HRD1)

Downstream transcription & fate

  • ATF4、CHOP（DDIT3）、XBP1s 驱动的恢复或促凋亡程序
  • Crosstalk with NF-κB, MAPK, autophagy (e.g., BECN1 context)

Supplement: ER-stress targets (gene symbols)

HGNC symbols for UPR sensors, chaperones/ERAD, integrated stress, and downstream outputs.

UPR sensors

UPR sensors (three arms)

EIF2AK3, ERN1, ATF6, ATF6B

Chaperones & ERAD

Translation stress

Integrated stress & translation

EIF2S1, ATF4, DDIT3, PPP1R15A, PPP1R15B, GADD34

Downstream transcription

UPR transcriptional outputs

XBP1, DNAJB9, HERPUD1, ASNS, WARS, ATF3, DDIT3

2. Suggested experimental readouts

For inducers (e.g., thapsigargin), titrate dose and time; for phospho-antibodies, pair totals and kinase-inhibitor controls.

  • p-PERK, p-eIF2α (Ser51), total PERK / eIF2α
  • XBP1s (RT-PCR or protein); IRE1α oligomerization / phospho (model-dependent)
  • ATF4 and CHOP nuclear accumulation; cleaved ATF6(N) (shift/IF)
  • BiP/GRP78 induction; ERAD gene panels (EDEM, HERPUD1, etc.)
  • Caspase-3/7, PARP cleavage—pair with apoptosis endpoints

3. UPR branch comparison

ArmSensorKey outputsNotes
PERKEIF2AK3p-eIF2α → ATF4 → CHOPISRIB-class tools modulate integrated stress readouts.
IRE1αERN1XBP1s；RIDDIRE1 RNase inhibitors for branch specificity.
ATF6ATF6（全长 ER 膜）Golgi cleavage → nuclear transcriptionOften parallels chaperone/ERAD induction.

4. Physiologic & pathologic context

  • Secretory & plasma cells: Adaptive UPR under high secretory load; XBP1s dependencies in secretory cancer states.
  • Metabolism & obesity: Hepatocyte/adipocyte ER stress links to insulin resistance and lipotoxicity.
  • Neurodegeneration: Protein aggregates and chronic UPR; branch balance determines protective vs toxic programs.

ER stress / UPR–related antibodies (curated)

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5. Product lines & on-site search

Primary & phospho antibodies

GRP78/BiP, calnexin, PDI, PERK, p-PERK, p-eIF2α, ATF4, CHOP, IRE1α, XBP1, ATF6, caspase-3—WB/IHC/IF.

Tool compounds & inducers

Classical inducers (thapsigargin, tunicamycin, DTT) and PERK/IRE1 inhibitors—for research per datasheets/ethics.

6. Inhibitors & tool compounds (summary)

For research use; follow lab SOP, compound datasheets, and ethics approvals.

GSK2606414

PERK kinase-domain inhibitor; probe PERK arm dependency.

ISRIB

ISR modulator; reframes p-eIF2α downstream readouts.

4μ8C / MKC8866

IRE1 RNase inhibitors; block XBP1 splicing.

Ceapin-A7

ATF6-arm research tool (literature-dependent).

Thapsigargin

SERCA inhibitor; canonical ER calcium-depletion stressor.

Tunicamycin

N-linked glycosylation inhibitor; disrupts glycoprotein folding.

Subtilase cytotoxin

S1P-dependent ATF6 cleavage models (pathogenesis research).

KIRA6

IRE1 kinase inhibitor (distinct from RNase blockers).

7. Pathway schematic

UPR three-arm schematic (conceptual)
ER stress and UPR schematic
Legend
  1. Unfolded proteins titrate BiP off transmembrane sensors
  2. Parallel activation of PERK / IRE1α / ATF6
  3. Transcriptional/translational reprogramming to restore ER function
  4. Failure switches CHOP/caspase pro-apoptotic programs

8. Pathway biology overview

The UPR is a central adaptive response to proteotoxic ER stress, crosstalking with lipid metabolism, calcium signaling, and autophagy initiation. In cancer, the UPR can support secretory proteostasis yet be co-opted for survival under nutrient stress—interpret with secretory burden, genetics, and therapy context.

  • IRE1α–JNK can couple to inflammasome/NF-κB programs
  • PERK intersects mTOR/ISR under amino-acid limitation

9. Related pathways on this site

Unfolded protein responseAutophagyApoptosisMAPK/ERKNF-κBInflammationPI3K/Akt/mTORJAK-STAT

10. External databases & modification resources

11. References

UPR mechanisms

  • • Walter P, Ron D. (2011). The unfolded protein response: from stress pathway to homeostatic regulation. Science. 334(6059):1081-6.
  • • Hetz C, Papa FR, Glimcher LH. (2015). The unfolded protein response in immunity and inflammation. Nat Rev Immunol. 15(8):469-84.

Disease & therapeutic angles

  • • Wang M, Kaufman RJ. (2014). Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature. 529(7586):326-37.
  • • Almanza A, et al. (2019). Endoplasmic reticulum stress signalling—from basic mechanisms to clinical applications. FEBS J. 286(2):241-278.