Mutants in the gene encoding mitochondrion-associated protein LRPPRC were found to be associated with French Canadian Type Leigh syndrome, a human disorder characterized with neurodegeneration and cytochrome c oxidase deficiency. LRPPRC interacts with one of microtubule-associated protein family MAP1S that promotes autophagy initiation and maturation to suppress genomic instability and tumorigenesis. Previously, although various studies have attributed LRPPRC nuclear acid-associated functions, we characterized that LRPPRC acted as an inhibitor of autophagy in human cancer cells. Here we show that liver-specific deletion of LRPPRC causes liver-specific increases of YAP and P27 and decreases of P62, leading to an increase of cell polyploidy and an impairment of autophagy maturation. The blockade of autophagy maturation and promotion of polyploidy caused by LRPPRC depletion synergistically enhances diethylnitrosamine-induced DNA damage, genome instability, and further tumorigenesis so that LRPPRC knockout mice develop more and larger hepatocellular carcinomas and survive a shorter lifespan. Therefore, LRPPRC suppresses genome instability and hepatocellular carcinomas and promotes survivals in mice by sustaining Yap-P27-mediated cell ploidy and P62-HDAC6-controlled autophagy maturation.

中文翻译：

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LRPPRC维持Yap-P27介导的细胞倍性和P62-HDAC6介导的自噬成熟，并抑制基因组不稳定和肝细胞癌。

发现编码线粒体相关蛋白LRPPRC的基因中的突变与法裔加拿大Leigh综合征有关，后者是一种以神经变性和细胞色素C氧化酶缺乏为特征的人类疾病。LRPPRC与微管相关蛋白家族MAP1S之一相互作用，后者促进自噬的起始和成熟，从而抑制基因组的不稳定性和肿瘤的发生。以前，尽管各种研究都归因于LRPPRC核酸相关功能，但我们的特征是LRPPRC充当人类癌细胞中自噬的抑制剂。在这里，我们显示LRPPRC的肝脏特异性缺失导致YAP和P27的肝脏特异性增加以及P62的减少，从而导致细胞多倍体性增加和自噬成熟受损。LRPPRC耗尽引起的自噬成熟的阻断和多倍体的促进协同增强了二乙基亚硝胺诱导的DNA损伤，基因组不稳定性和进一步的肿瘤发生，从而使LRPPRC敲除小鼠发展为越来越大的肝细胞癌，并存活较短的寿命。因此，LRPPRC通过维持Yap-P27介导的细胞倍性和P62-HDAC6控制的自噬成熟来抑制基因组不稳定和肝细胞癌，并提高小鼠的存活率。