Mutation in FBXO32 causes dilated cardiomyopathy through up-regulation of ER-stress mediated apoptosis.

ABSTRACT: Endoplasmic reticulum (ER) stress induction of cell death is implicated in cardiovascular diseases. Sustained activation of ER-stress induces the unfolded protein response (UPR) pathways, which in turn activate three major effector proteins. We previously reported a missense homozygous mutation in FBXO32 (MAFbx, Atrogin-1) causing advanced heart failure by impairing autophagy. In the present study, we performed transcriptional profiling and biochemical assays, which unexpectedly revealed a reduced activation of UPR effectors in patient mutant hearts, while a strong up-regulation of the CHOP transcription factor and of its target genes are observed. Expression of mutant FBXO32 in cells is sufficient to induce CHOP-associated apoptosis, to increase the ATF2 transcription factor and to impair

SUBMITTER: Al-Yacoub N 

PROVIDER: S-EPMC8285540 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature