Growth arrest and DNA damage-inducible protein 34-Protein phosphatase 1 complex (GADD34:PP1 complex)

The Growth arrest and DNA damage-inducible protein 34-Protein phosphatase 1 (GADD34:PP1) complex is a specialized enzymatic assembly that plays a pivotal role in the termination of the Integrated Stress Response (ISR) (UniProt: P17564). It consists of the regulatory subunit GADD34, encoded by the PPP1R15A gene, and the catalytic subunit of Protein Phosphatase 1 (PP1) (PubMed: 11847340). The primary biological function of this complex is the dephosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2α), which is a critical step in restoring global protein synthesis following cellular stress (PubMed: 11274165). Dysregulation of the GADD34:PP1 complex is associated with various diseases, including neurodegenerative disorders like Amyotrophic Lateral Sclerosis (ALS) and Alzheimer's, as well as cancer and viral infections (PubMed: 25859043). Pharmacological inhibition of this complex, using agents such as Guanabenz or Sephin1, is being explored as a therapeutic strategy to prolong eIF2α phosphorylation, thereby enhancing cellular proteostasis and protecting against the accumulation of misfolded proteins (PubMed: 21575858). However, therapeutic intervention must balance the benefits of stress response prolongation against the potential risks of sustained translation inhibition (PubMed: 25859043).

Other names

PPP1R15A:PP1 complexGADD34-PP1c complexeIF2α phosphatase complexGrowth arrest and DNA damage-inducible protein 34-Protein phosphatase 1 catalytic subunit complex

Selective inhibition of the GADD34 regulatory subunit prevents the recruitment of the PP1 catalytic subunit to its substrate, phosphorylated eIF2α, thereby maintaining the integrated stress response and protecting cells from proteotoxic stress (PubMed: 25859043).