Santos, C.C., Schweizer, N., Cairrão, F., Ramirez, J., Osinalde, N., Yang, M., Gaspar, C.J., Rasheva, V.I., Trigo, M.L., Hensel, Z., Adrain, C., Cordeiro, T.N., Voigt, F., Gameiro, P.A., Mayor, U., Domingos, P.M. (2025). Fbxo42 promotes the degradation of Ataxin-2 granules to trigger terminal Xbp1 signaling.  Nat. Commun. 16(1): 7523.

FBrf0263179

Research paper

The Unfolded Protein Response (UPR) is activated by the accumulation of misfolded proteins in the Endoplasmic Reticulum (ER), a condition known as ER stress. Prolonged ER stress and UPR activation cause cell death, by mechanisms that remain poorly understood. Here, we report that regulation of Ataxin-2 by Fbxo42 is a crucial step during UPR-induced cell death. From a genetic screen in Drosophila, we identify loss of function mutations in Fbxo42 that suppress cell death and retinal degeneration induced by the overexpression of Xbp1[spliced], an important mediator of the UPR. We identify the RNA binding protein Ataxin-2 as a substrate of Fbxo42, which, as part of a Skp-A/Cullin-1 complex, promotes the ubiquitylation and degradation of Ataxin-2. Upon ER-stress, the mRNA of Xbp1 is sequestered and stabilized in Ataxin-2 granules, where it remains untranslated. Fbxo42 recruitment to these granules promotes the degradation of Ataxin-2, allowing for the translation of Xbp1 mRNA and triggering cell death during the terminal stages of UPR activation.

PMC12350939 (PMC) (EuropePMC)