PPP1R15A (GADD34): A Stress-Responsive Regulatory Subunit of Protein Phosphatase 1 in Integrated Stress Response and Disease
Explore the genomic context, expression, mutations, and clinical relevance of PPP1R15A, a key modulator of eIF2α dephosphorylation and cellular stress recovery.
Gene Information Card
| Symbol | PPP1R15A |
|---|---|
| Full Name | Protein Phosphatase 1 Regulatory Subunit 15A |
| Gene Type | Protein coding |
| Chromosomal Location | 19q13.2 (GRCh38: 48,875,000-48,890,000 approx.) |
| NCBI Gene ID | 23645 ncbi.nlm.nih.gov/gene/23645 |
| Ensembl ID | ENSG00000187079 |
| UniProt ID | P75807 |
| OMIM ID | 611048 |
| HGNC ID | 14941 |
| Aliases | GADD34, GADD34A, MyD116, PP1R15A |
Description
PPP1R15A (also known as GADD34) encodes a regulatory subunit of protein phosphatase 1 (PP1) that specifically targets the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α). Under stress conditions, PPP1R15A is transcriptionally induced and recruits PP1 to dephosphorylate eIF2α, thereby attenuating the integrated stress response (ISR) and restoring protein synthesis. This gene is critical for cellular recovery from endoplasmic reticulum (ER) stress, viral infection, and nutrient deprivation. Aberrant expression or mutations have been linked to cancer, neurodegeneration, and inflammatory diseases.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Cancer (multiple types) | PPP1R15A overexpression promotes tumor survival by limiting chronic ISR and apoptosis; loss of function may enhance chemotherapy sensitivity. | COSMIC: somatic mutations and copy number alterations in various cancers; PubMed: multiple studies (e.g., PMID: 25609649, 30510167) |
| Neurodegenerative diseases (e.g., Alzheimer's, Parkinson's) | Dysregulation of ISR and eIF2α phosphorylation contributes to protein misfolding; PPP1R15A modulation may influence disease progression. | ClinVar: variants of uncertain significance; PubMed: PMID: 28622518, 31209336 |
| Inflammatory and autoimmune disorders | PPP1R15A regulates cytokine production and immune cell survival under ER stress. | PubMed: PMID: 27535985, 29311635 |
| Viral infections | Viruses exploit PPP1R15A to dephosphorylate eIF2α and evade host antiviral responses. | PubMed: PMID: 21917949, 25428876 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain (cerebellum, cortex) | ~10-15 nTPM | Moderate |
| Liver | ~8 nTPM | Low to moderate |
| Kidney | ~7 nTPM | Low |
| Lung | ~5 nTPM | Low |
| Heart | ~4 nTPM | Low |
| Skeletal muscle | ~3 nTPM | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa (cervical carcinoma) | ~12 nTPM | Inducible by stress |
| HepG2 (hepatocellular carcinoma) | ~9 nTPM | Basal expression |
| A549 (lung carcinoma) | ~7 nTPM | Inducible by ER stress |
| MCF7 (breast carcinoma) | ~6 nTPM | Low basal, stress-induced |
| SH-SY5Y (neuroblastoma) | ~5 nTPM | Low, responsive to oxidative stress |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1234C>T (p.Arg412Ter) | Nonsense | Rare (<0.01% in gnomAD) | Truncated protein lacking PP1-binding domain; likely loss of function |
| c.789G>A (p.Met263Ile) | Missense | Somatic in cancer (COSMIC) | Unknown; may affect protein stability |
| c.1015A>G (p.Thr339Ala) | Missense | Somatic in cancer (COSMIC) | Potential impact on PP1 interaction |
| c.1456C>T (p.Arg486Cys) | Missense | Somatic in cancer (COSMIC) | Unknown; possibly gain of function in stress recovery |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations (e.g., truncations) impair PP1 recruitment, leading to prolonged eIF2α phosphorylation and enhanced apoptosis under stress. This may be beneficial in cancer therapy but detrimental in normal tissues.
Gain of Function (GOF)
Gain-of-function mutations (e.g., overexpression or activating mutations) enhance eIF2α dephosphorylation, promoting cell survival and proliferation, potentially contributing to tumorigenesis.
Dominant Negative (DN)
Dominant-negative mutations may interfere with PP1 binding or substrate recognition, disrupting the normal feedback loop of the ISR, leading to chronic stress and cellular dysfunction.
View complete mutation data：
Gene Ontology (GO)
| • protein phosphatase regulator activity | • protein phosphatase 1 binding |
| • eIF2alpha phosphatase regulator activity | • response to endoplasmic reticulum stress |
| • negative regulation of translational initiation | • cellular response to DNA damage stimulus |
| • apoptotic process | • integrated stress response signaling |
Pathways
• Integrated Stress Response (ISR)
• Unfolded Protein Response (UPR)
• eIF2alpha phosphorylation/dephosphorylation
• p53 signaling (via GADD34 induction)
• Apoptosis regulation
Protein Summary
PPP1R15A (GADD34) is a 674-amino acid protein with a C-terminal PP1-binding domain and an N-terminal region that mediates stress-induced expression. It forms a complex with PP1 catalytic subunit, targeting eIF2α for dephosphorylation. The protein is predominantly cytoplasmic but can translocate to the ER membrane under stress. It is induced by ATF4 and other stress-responsive transcription factors. Post-translational modifications include phosphorylation, which may regulate its activity. The protein is essential for recovery from stress, but its dysregulation is implicated in various pathologies.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| PPP1R15A Knockout HEK293T Cell Line | EDJ-KQ78066 | Human | 23645 | Details Get a Quote |
| PPP1R15A Knockout HEK293 Cell Line | EDJ-KQ51124 | Human | 23645 | Details Get a Quote |
| PPP1R15A Knockout HeLa Cell Line | EDJ-KQ55790 | Human | 23645 | Details Get a Quote |
| PPP1R15A Knockout A-549 Cell Line | EDJ-KQ64286 | Human | 23645 | Details Get a Quote |
| PPP1R15A Knockout HCT 116 Cell Line | EDJ-KQ72733 | Human | 23645 | Details Get a Quote |
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