Protein phosphatase 1 regulatory subunit 15A–Protein phosphatase 1 catalytic subunit complex (PPP1R15A–PP1c)

The PPP1R15A–PP1c holophosphatase complex is a specialized enzyme assembly responsible for terminating the integrated stress response (ISR) by dephosphorylating the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) (UniProt P17564). The complex is composed of the stress-inducible regulatory subunit PPP1R15A (also known as GADD34) and the catalytic subunit of protein phosphatase 1 (PP1c) (Science, 2011, 332(6032):915-917). By restoring protein synthesis after a period of cellular stress, such as endoplasmic reticulum stress or nutrient deprivation, the complex plays a critical role in cellular recovery and homeostasis. In the context of neurodegenerative and protein-misfolding diseases, inhibiting this complex has emerged as a therapeutic strategy to prolong the protective effects of eIF2α phosphorylation, which reduces the global rate of translation and allows cells to better manage misfolded protein loads (Science, 2015, 348(6231):239-242). Small molecules like Sephin1 (IFB-088) and Guanabenz have demonstrated the ability to selectively target this complex, offering a potential path for treating conditions like Amyotrophic Lateral Sclerosis (ALS) and Charcot-Marie-Tooth disease. However, therapeutic development faces challenges regarding the selectivity of inhibitors to avoid affecting the constitutive PPP1R15B–PP1c complex, which is essential for normal cellular function and survival. Overall, the PPP1R15A–PP1c complex represents a pivotal node in the cellular proteostasis network and a high-interest target for modulating the ISR in various pathologies.

Other names

GADD34–PP1c complexPPP1R15A–PP1 complexGrowth arrest and DNA damage-inducible protein GADD34–PP1c complexGADD34–Protein phosphatase 1 complexeIF2α-P phosphatase complex

Selective inhibition of the PPP1R15A-mediated dephosphorylation of eIF2α to prolong the integrated stress response and enhance cellular proteostasis.