DISC1 promotes translation maintenance during sodium arsenite-induced oxidative stress

Fuentes-Villalobos, Francisco; Farkas, Carlos; Riquelme-Barrios, Sebastián; Armijo, Marisol E.; Soto-Rifo, Ricardo; Pincheira, Roxana; Castro, Ariel F.

doi:10.1016/j.bbagrm.2019.05.001

Cited by 6 publications

(10 citation statements)

References 44 publications

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“…16,17 In the present study, we examine the molecular basis of the recently reported ability of DISC1 to both detect and orchestrate the cellular response to oxidative stress induced by arsenic. 15 The presence of a cysteine motif (C-X-C-X-C) in the Cterminal domain of DISC1 led us to investigate whether DISC1 could directly bind to arsenic. DISC1 C-terminal domain is especially relevant from a pathophysiological perspective because it encompasses polymorphisms recognized as risk factors for mental illness, such as the S704C and L807-frameshift mutant.…”

Section: Discussionmentioning

confidence: 99%

“…[11][12] Interestingly, the role of DISC1 as a translational inhibitor is reversed when cells are treated with sodium arsenite, inducing oxidative stress. 15 Indeed, in oxidative stress conditions, DISC1 appears to act as a general enhancer of protein synthesis by interacting with eiF3, a key component of the translational machinery that recruits the small ribosomal subunit 40S (Fig. 1B).…”

Section: Introductionmentioning

confidence: 99%

“…14 Furthermore, a recent study by Fuentes-Villalobos et al has highlighted the role of DISC1 in maintaining homeostatic control of protein synthesis during oxidative stress. 15 In non-stress conditions DISC1 acts as an overall inhibitor of the Akt/mTOR pathway by sequestering the activator girdin, therefore exerting a negative control on the translation processes associated with this pathway (Fig. 1A).…”

Section: Introductionmentioning

confidence: 99%

“…1B). 14,15 The study by Fuentes-Villalobos et al therefore suggests that DISC1 is required for rescuing protein synthesis under oxidative stress conditions. 15 Yet the molecular mechanisms underlying the switch of DISC1 function from a general inhibitor to an activator of protein synthesis remain elusive.…”

Section: Introductionmentioning

confidence: 99%

“…14,15 The study by Fuentes-Villalobos et al therefore suggests that DISC1 is required for rescuing protein synthesis under oxidative stress conditions. 15 Yet the molecular mechanisms underlying the switch of DISC1 function from a general inhibitor to an activator of protein synthesis remain elusive. Bioinformatics analysis suggest that DISC1 is composed of a predominantly disordered N-terminal domain (residues 1-350) and a helical C-terminal domain (residues 351-854).…”

Section: Introductionmentioning

confidence: 99%

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Evidence of Disrupted-in Schizophrenia 1 (DISC1) as an arsenic binding protein and implications regarding its role as a translational activator

Watanabe,

Khu,

Warren

et al. 2023

Preprint

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Disrupted-in-schizophrenia-1 (DISC1) is a scaffold protein that plays a pivotal role in orchestrating signaling pathways involved in neurodevelopment, neural migration, and synaptogenesis. Among those, it has recently been reported that the role DISC1 in the Akt/mTOR pathway can shift from a global translational repressor to a translational activator in response to oxidative stress induced by arsenic. In this study we are providing evidence that DISC1 can directly bind arsenic via a C-terminal cysteine motif (C-X-C-X-C). A series of fluorescence-based binding assays were conducted with a truncated C-terminal domain construct of DISC1 and a of series of single, double, and triple cysteine mutants. We found that arsenous acid, a trivalent arsenic derivative, specifically binds to the C-terminal cysteine motif of DISC1 with low micromolar affinity. All three cysteines of the motif are required for high-affinity binding. Electron microscopy experiments combined with in silico structural predictions revealed that that the C-terminal of DISC1 forms an elongated tetrameric complex. The cysteine motif is consistently predicted to be located within a loop, fully exposed to solvent, providing a simple molecular framework to explain the high-affinity of DISC1 toward arsenous acid. This study sheds light on a novel functional facet of DISC1 as an arsenic binding protein and highlights its potential role as both a sensor and translational modulator within the Akt/mTOR pathway.

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Section: Discussionmentioning

confidence: 99%