Mutation in FBXO32 causes dilated cardiomyopathy through up-regulation of ER-stress mediated apoptosis.
Mutation in FBXO32 causes dilated cardiomyopathy through up-regulation of ER-stress mediated apoptosis.
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FBXO32基因的突变通过上调内质网应激介导的细胞凋亡，引发扩张型心肌病。
DOI：
10.1038/s42003-021-02391-9
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发表时间：
2021-07-16
影响因子：
5.9
通讯作者：
Poizat C
中科院分区：
文献类型：
--
作者：
Al-Yacoub N;Colak D;Mahmoud SA;Hammonds M;Muhammed K;Al-Harazi O;Assiri AM;Al-Buraiki J;Al-Habeeb W;Poizat C
内质网应激诱导细胞死亡与心血管疾病有关。持续激活内质网应激诱导未折叠蛋白反应（UPR）途径，进而激活三种主要的效应蛋白。我们之前报道了FBXO32 （MAFbx, Atrogin-1）的错义纯合突变，通过损害自噬导致晚期心力衰竭。在本研究中，我们进行了转录分析和生化分析，出乎意料地揭示了UPR效应物在患者突变心脏中的激活减少，而CHOP转录因子及其靶基因的强烈上调被观察到。突变体FBXO32在细胞中的表达足以诱导chop相关的凋亡，增加ATF2转录因子并损害ATF2泛素化。ATF2蛋白在人类心脏中与FBXO32相互作用，在FBXO32突变心脏中表达特别高。这些发现为fbxo32介导的心肌病提供了一种新的潜在机制，可能涉及CHOP的异常激活。这些结果表明，CHOP激活的其他非规范途径可能被认为是治疗fbxo32相关DCM的新治疗靶点。Al-Yacoub等人研究了FBXO32突变对扩张型心肌病的影响。研究发现，内质网应激、CHOP异常激活和CHOP诱导的细胞凋亡是FBXO32突变诱导心肌病的基础，而UPR效应物没有激活，这表明可以考虑另一种途径来开发新的治疗靶点。
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.
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影响因子：
2.7
作者：
Guo XF;Yang XJ
通讯作者：
Yang XJ
影响因子：
37.8
作者：
Kehat I;Molkentin JD
通讯作者：
Molkentin JD
影响因子：
21.3
作者：
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影响因子：
12.3
作者：
Al-Yacoub N;Shaheen R;Awad SM;Kunhi M;Dzimiri N;Nguyen HC;Xiong Y;Al-Buraiki J;Al-Habeeb W;Alkuraya FS;Poizat C
通讯作者：
Poizat C
影响因子：
12.4
作者：
Kale J;Osterlund EJ;Andrews DW
通讯作者：
Andrews DW