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

The Protein phosphatase 1 regulatory subunit 15A (PPP1R15A)-Protein phosphatase 1 catalytic subunit (PP1c) complex is a key phosphatase assembly involved in the termination of the integrated stress response (ISR). The regulatory subunit, PPP1R15A (also known as GADD34), is transcriptionally induced during cellular stress and recruits the catalytic subunit of protein phosphatase 1 (PP1c) to specifically dephosphorylate the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) [UniProt: P17564]. This dephosphorylation event reverses the global inhibition of protein synthesis, allowing the cell to resume normal translation after the stress has been addressed. In the context of neurodegenerative diseases and proteotoxicity, the premature resumption of protein synthesis can be detrimental, leading to the accumulation of misfolded proteins and subsequent cell death [PubMed: 25859043]. Therapeutic targeting of the PPP1R15A-PP1c complex aims to selectively inhibit its phosphatase activity, thereby prolonging eIF2α phosphorylation and maintaining a state of reduced protein synthesis that favors cellular recovery and proteostasis. Small molecules such as Guanabenz and its non-adrenergic derivative Sephin1 (IFB-088) have demonstrated the ability to bind this complex and provide neuroprotection in models of Amyotrophic Lateral Sclerosis (ALS) and Charcot-Marie-Tooth disease [PubMed: 25859043, PubMed: 21525932]. However, because PP1c is involved in numerous other cellular processes, achieving high selectivity for the PPP1R15A-bound form is a significant pharmacological challenge to avoid systemic toxicity and off-target effects.

Other names

GADD34-PP1c complexPPP1R15A-PP1 complexGrowth arrest and DNA damage-inducible protein 34-Protein phosphatase 1 complexeIF2-alpha phosphatase complex

Selective inhibition of the PPP1R15A-PP1c complex to prevent the dephosphorylation of eIF2-alpha, thereby prolonging the integrated stress response and reducing the rate of protein synthesis to alleviate proteotoxic stress [PubMed: 25859043].