Mutation in FBXO32 causes dilated cardiomyopathy through up-regulation of ER-stress mediated apoptosis
| Autor: | Kunhi Muhammed, Abdullah M. Assiri, Dilek Colak, Salma Awad Mahmoud, Maya Hammonds, Jehad Al-Buraiki, Waleed AlHabeeb, Olfat Al-Harazi, Coralie Poizat, Nadya Al-Yacoub |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cardiomyopathy Dilated Programmed cell death QH301-705.5 Cardiomyopathy Mutation Missense Cardiology Medicine (miscellaneous) Muscle Proteins Apoptosis CHOP Biology General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences 0302 clinical medicine medicine Genetics Biology (General) Transcription factor FBXO32 SKP Cullin F-Box Protein Ligases Endoplasmic reticulum Autophagy medicine.disease Endoplasmic Reticulum Stress Cell biology Up-Regulation Gene regulation 030104 developmental biology 030220 oncology & carcinogenesis Unfolded protein response biological phenomena cell phenomena and immunity General Agricultural and Biological Sciences |
| Zdroj: | Communications Biology, Vol 4, Iss 1, Pp 1-12 (2021) Communications Biology |
| ISSN: | 2399-3642 |
| Popis: | 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 ATF2 ubiquitination. ATF2 protein interacts with FBXO32 in the human heart and its expression is especially high in FBXO32 mutant hearts. These findings provide a new underlying mechanism for FBXO32-mediated cardiomyopathy, implicating abnormal activation of CHOP. These results suggest alternative non-canonical pathways of CHOP activation that could be considered to develop new therapeutic targets for the treatment of FBXO32-associated DCM. Al-Yacoub et al. investigate the consequences of FBXO32 mutation on dilated cardiomyopathy. ER stress, abnormal CHOP activation and CHOP-induced apoptosis with no UPR effector activation are found to underlie the FBXO32 mutation induced cardiomyopathy, suggesting an alternative pathway that can be considered to develop new therapeutic targets for its treatment. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
| Nepřihlášeným uživatelům se plný text nezobrazuje | K zobrazení výsledku je třeba se přihlásit. |