DISC1 promotes translation maintenance during sodium arsenite-induced oxidative stress

Biochim Biophys Acta Gene Regul Mech. 2019 Jun;1862(6):657-669. doi: 10.1016/j.bbagrm.2019.05.001. Epub 2019 May 7.


Variation in Disrupted-in-Schizophrenia 1 (DISC1) increases the risk for neurodegenerative diseases, schizophrenia, and other mental disorders. However, the functions of DISC1 associated with the development of these diseases remain unclear. DISC1 has been reported to inhibit Akt/mTORC1 signaling, a major regulator of translation, and recent studies indicate that DISC1 could exert a direct role in translational regulation. Here, we present evidence of a novel role of DISC1 in the maintenance of protein synthesis during oxidative stress. In order to investigate DISC1 function independently of Akt/mTORC1, we used Tsc2-/- cells, where mTORC1 activation is independent of Akt. DISC1 knockdown enhanced inhibition of protein synthesis in cells treated with sodium arsenite (SA), an oxidative agent used for studying stress granules (SGs) dynamics and translational control. N-acetyl-cysteine inhibited the effect of DISC1, suggesting that DISC1 affects translation in response to oxidative stress. DISC1 decreased SGs number in SA-treated cells, but resided outside SGs and maintained protein synthesis independently of a proper SG nucleation. DISC1-dependent stimulation of translation in SA-treated cells was supported by its interaction with eIF3h, a component of the canonical translation initiation machinery. Consistent with a role in the homeostatic maintenance of translation, DISC1 knockdown or overexpression decreased cell viability after SA exposure. Our data suggest that DISC1 is a relevant component of the cellular response to stress, maintaining certain levels of translation and preserving cell integrity. This novel function of DISC1 might be involved in its association with pathologies affecting tissues frequently exposed to oxidative stress.

Keywords: DISC1; G3BP1; Oxidative stress; Sodium arsenite; Stress granules; Translation; eIF3h.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arsenites / pharmacology*
  • Cell Survival / drug effects
  • Cytoplasmic Granules / metabolism
  • DNA Helicases / metabolism
  • Eukaryotic Initiation Factor-3 / metabolism
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Oncogene Protein v-akt
  • Oxidative Stress / drug effects*
  • Poly-ADP-Ribose Binding Proteins / metabolism
  • RNA Helicases / metabolism
  • RNA Recognition Motif Proteins / metabolism
  • Sodium Compounds / pharmacology*
  • Transcriptome
  • Tuberous Sclerosis Complex 2 Protein / genetics


  • Arsenites
  • DISC1 protein, human
  • Eukaryotic Initiation Factor-3
  • Nerve Tissue Proteins
  • Poly-ADP-Ribose Binding Proteins
  • RNA Recognition Motif Proteins
  • Sodium Compounds
  • TSC2 protein, human
  • Tuberous Sclerosis Complex 2 Protein
  • sodium arsenite
  • Mechanistic Target of Rapamycin Complex 1
  • Oncogene Protein v-akt
  • DNA Helicases
  • G3BP1 protein, human
  • RNA Helicases