Unfolded protein response (UPR)

The unfolded protein response (UPR) is a conserved program triggered when misfolded proteins exceed ER folding capacity. PERK, IRE1α, and ATF6 coordinately reprogram translation initiation, RNA splicing/decay, and transcription to expand chaperones and ERAD—while unresolved stress can steer branches toward CHOP-driven apoptosis, stress granules, and inflammatory coupling.

For ER luminal stress context (calcium, secretory load, folding QC), see the companion ER stress hub.

1. Key targets

UPR sensors & three canonical arms

  • 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: UPR targets (gene symbols)

Shared sensors link to ER-stress gene pages; see modules below.

UPR sensors

UPR sensors (shared with ER-stress hub)

EIF2AK3, ERN1, ATF6, HSPA5

UPR outputs

UPR transcriptional program

XBP1, ATF4, DDIT3, DNAJB9, EDEM1, HERPUD1, ASNS, WARS

Protein quality control

CANX, CALR, PDIA3, SEL1L, SYVN1, OS9

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. UPR in immunity, metabolism & cancer

  • Immunity & inflammation: IRE1α–TRAF2–JNK links to NF-κB/NLRP3 programs; DC maturation and antigen presentation are tuned by UPR.
  • Metabolic organs: PERK–ATF4 intersects amino-acid sensing and lipogenic programs; hepatic UPR crosstalks with insulin signaling.
  • Tumor dependencies & therapy: Secretory/hypoxic tumors can co-opt XBP1s/ATF4 for proteostasis; PERK/IRE1 co-targeting with chemo/IO needs careful readout design.

Unfolded protein response (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)
Unfolded protein response (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 fundamentally a tunable transcriptional/translational program: the same sensors can favor homeostatic repair acutely yet shift toward pro-inflammatory or pro-apoptotic outputs when branches are chronically imbalanced. It intersects the integrated stress response at eIF2α phosphorylation and co-decides cell fate with mTOR/AMPK nutrient sensing.

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

9. Related pathways on this site

ER stressAutophagyApoptosisMAPK/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.