Protein phosphatase 1 regulatory subunit 15A–Protein phosphatase 1 complex (PPP1R15A–PP1 complex)

The Protein phosphatase 1 regulatory subunit 15A (PPP1R15A)–Protein phosphatase 1 (PP1) complex is a specialized enzymatic assembly that regulates the phosphorylation state of the eukaryotic translation initiation factor 2 subunit alpha (eIF2α) (UniProt O75807). PPP1R15A, also known as GADD34, is a stress-inducible regulatory subunit that recruits the catalytic subunit of PP1 to specifically dephosphorylate eIF2α, acting as a critical negative feedback loop in the integrated stress response (ISR) (PubMed: 21493862). By dephosphorylating eIF2α, the complex restores general protein synthesis after a period of cellular stress, such as endoplasmic reticulum (ER) stress or viral infection. In various neurodegenerative conditions, the ISR is chronically activated; pharmacological inhibition of the PPP1R15A–PP1 complex aims to prolong eIF2α phosphorylation to enhance the cell's proteostatic capacity and provide neuroprotection (PubMed: 25763591). Small molecules like Sephin1 and Guanabenz have been developed to selectively target this complex, offering a therapeutic strategy to treat protein misfolding diseases by extending the window of reduced protein synthesis and increased chaperone expression (Science, 2015, 348(6231):239-242).

Other names

GADD34–PP1 complexGrowth arrest and DNA damage-inducible protein 34–Protein phosphatase 1 complexeIF2α phosphatase complexPPP1R15A-PP1 phosphatase

Selective inhibition of the PPP1R15A regulatory subunit to prevent the dephosphorylation of eIF2α, thereby prolonging the cytoprotective integrated stress response.