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Fbxo42 promotes the degradation of Ataxin-2 granules to trigger terminal Xbp1 signaling

Cristiana C Santos1, Nadine Schweizer1, Fátima Cairrão1

  • 1Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal.

Nature Communications
|August 13, 2025
PubMed

Insights

Fbxo42 regulates Ataxin-2 during the Unfolded Protein Response (UPR). This mechanism controls Xbp1 mRNA translation, impacting cell death following Endoplasmic Reticulum stress.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • The Unfolded Protein Response (UPR) mitigates Endoplasmic Reticulum (ER) stress caused by misfolded proteins.
  • Sustained ER stress and UPR activation can lead to cell death through incompletely understood pathways.

Purpose of the Study:

  • To elucidate the molecular mechanisms governing UPR-induced cell death.
  • To identify novel regulators of the UPR pathway.

Main Methods:

  • Utilized Drosophila genetic screening to identify suppressors of UPR-induced cell death.
  • Investigated the interaction between Fbxo42 and Ataxin-2.
  • Analyzed the role of Ataxin-2 in Xbp1 mRNA regulation during ER stress.

Main Results:

  • Loss-of-function mutations in Fbxo42 suppressed cell death and retinal degeneration induced by Xbp1spliced overexpression.
  • Identified Ataxin-2 as an Fbxo42 substrate, promoting its ubiquitylation and degradation via a Skp-A/Cullin-1 complex.
  • Demonstrated that Fbxo42 promotes Ataxin-2 degradation, enabling Xbp1 mRNA translation and triggering cell death.

Conclusions:

  • Fbxo42-mediated Ataxin-2 regulation is critical for UPR-induced cell death.
  • Ataxin-2 sequesters and stabilizes Xbp1 mRNA in granules, preventing translation during ER stress.
  • Fbxo42 facilitates the release of Xbp1 mRNA for translation, driving terminal UPR-induced cell death.

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