Protein phosphatase 1 regulatory subunit 15A (PPP1R15A) (PPP1R15A)

Protein phosphatase 1 regulatory subunit 15A (PPP1R15A), commonly known as GADD34, is a stress-inducible protein that acts as a regulatory subunit for the catalytic subunit of protein phosphatase 1 (PP1c) (UniProt P17564). The primary function of the PPP1R15A/PP1c complex is to dephosphorylate the alpha subunit of eukaryotic translation initiation factor 2 (eIF2-alpha), which reverses the global translation inhibition initiated during the Integrated Stress Response (ISR) (PubMed: 21529741). This feedback mechanism is essential for cellular recovery following endoplasmic reticulum (ER) stress, but its premature activation can be detrimental in conditions of chronic proteotoxic stress, such as neurodegenerative diseases (PubMed: 25768908). Small molecules like Guanabenz and its derivative Sephin1 (IFB-088) have been identified as selective inhibitors of the PPP1R15A/PP1c complex, effectively prolonging eIF2-alpha phosphorylation to protect cells from misfolded protein accumulation (PubMed: 21529741, PubMed: 25768908). Targeting this complex is currently being explored for the treatment of Amyotrophic Lateral Sclerosis (ALS) and Charcot-Marie-Tooth disease (ClinicalTrials.gov: NCT03610334). However, therapeutic challenges include the risk of inducing apoptosis through the CHOP pathway if the ISR is sustained for too long, as well as ensuring selectivity over the constitutive isoform PPP1R15B (PubMed: 25768908).

Other names

GADD34Growth arrest and DNA damage-inducible protein 34Myeloid differentiation primary response protein MyD116 homolog

Selective inhibition of the PPP1R15A/PP1c complex to prevent the dephosphorylation of eIF2-alpha, thereby prolonging the Integrated Stress Response and enhancing cellular proteostasis.