Role of m6A modification in Alpha 1-antitrypsin deficiency induces liver disease

项目总结 α1抗胰蛋白酶缺乏症(AATD)是中国人肝病最常见的遗传原因 儿童和最常见的遗传性肝功能衰竭和肝移植指征 儿科人口。然而，AATD相关肝病的临床病程是高度可变的。 大多数纯合子重度AATD(PIZZ)婴儿在儿童早期临床康复 通过未知的适应机制。流行病学研究产生了三个 该领域的悬而未决的问题。它们是：(1)有哪些适应机制 错误折叠的AAT在内质网管腔中的积聚？(2)只有适应机制 对错误折叠的AAT的反应，还是也针对其他未折叠的蛋白质？以及(3)我们是否可以设计 直接使用这些适应机制的治疗策略？在这里，我们确定了一部小说 α1-抗胰蛋白酶缺乏适应机制，内质网蛋白毒性应激-m6A途径或ERm6A ：未折叠的α1-抗胰蛋白酶蛋白积聚诱导N6-腺苷-甲基转移酶14 (METTL14)上调以增加C/EBP同源蛋白(CHOP)的m6A mRNA甲基化， 其抑制CHOP翻译并减少其下游促凋亡基因的表达 靶基因、细胞凋亡和肝损伤。我们认为ERm6A调节内质网蛋白毒性应激 在转录水平上，通过一种与以前任何其他机制不同的机制 描述了内质网蛋白毒性应激相关的信号通路，包括众所周知的 规范的(转录和翻译水平)UPR途径。我们将检验中心假说 由未折叠蛋白积累诱导的METTL14抑制细胞死亡和肝脏 肝脏毒性(AIM 1.1)通过调节CHOP 5‘UTRm6A修饰(AIM 1.2)。这项建议 通过严格研究NICHD的分子机制来解决NICHD的任务 AATD导致的肝损伤，有可能改善大量儿童的健康。

PROJECT SUMMARY Alpha1-antitrypsin deficiency (AATD) is the most common genetic cause of liver disease in children and the most frequent inherited indication for liver failure and transplantation in the pediatric population. However, the clinical course of AATD-related liver disease is highly variable. The majority of infants with homozygous severe AATD (PiZZ) clinically recover in early childhood through the unknown adaptive mechanisms. Epidemiological studies give rise to three outstanding questions in the field. They are: (1) What are the mechanisms of adaptation to the misfolded AAT accumulation in the lumen of ER? (2) Do the mechanisms of adaptation only response to misfolded AAT or also target other unfolded proteins? and (3) Can we design therapeutic strategies to directly use these mechanisms of adaptation? Here, we identified a novel alpha1-antitrypsin deficiency adaptive mechanism, ER proteotoxic stress-m6A pathway or ERm6A : Unfolded Alpha1-antitrypsin protein accumulation induces N6-adenosine-methyltransferase 14 (METTL14) elevation to increase m6A mRNA methylation of C/EBP Homologous Protein (CHOP), which suppresses CHOP translation and reduces expression of its downstream pro-apoptotic target genes, apoptosis and liver injury. We propose that ERm6A regulates ER proteotoxic stress at the epitranscriptional level, through a mechanism that is distinct from any other previously described ER proteotoxic stress-associated signaling pathway, including the well-known canonical (transcriptional and translational level) UPR pathway. We will test the central hypothesis that METTL14, induced by unfolded protein accumulation, suppresses cell death and liver hepatotoxicity (Aim 1.1) by modulating CHOP 5′ UTR m6A modification (Aim 1.2). This proposal addresses the mission of the NICHD by rigorously investigating the molecular mechanisms of AATD-induced liver injury with the potential to improve health for large numbers of children.