Fanconi Anemia Proteins Function in Mitophagy and Immunity.
Fanconi Anemia Proteins Function in Mitophagy and Immunity.
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Fanconi贫血蛋白在线粒体和免疫力中起作用。
DOI：
10.1016/j.cell.2016.04.006
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发表时间：
2016-05-05
期刊：
影响因子：
64.5
通讯作者：
Levine B
中科院分区：
文献类型：
--
作者：
Sumpter R Jr;Sirasanagandla S;Fernández ÁF;Wei Y;Dong X;Franco L;Zou Z;Marchal C;Lee MY;Clapp DW;Hanenberg H;Levine B
范可尼贫血（FA）通路基因是重要的肿瘤抑制因子，其最具特征的功能是修复受损的核DNA。在此，我们描述了FA基因在两种形式的选择性自噬中的重要作用。Fancc的基因缺失阻断了病毒的自噬清除（病毒吞噬），并增加了对致死性病毒性脑炎的易感性。FANCC与Parkin互动;在体外和体内需要清除受损的线粒体;并减少线粒体ROS的产生和炎性小体的活化。FANCC的线粒体自噬功能在遗传上与其在基因组DNA损伤修复中的作用不同。此外，FA途径中的其他基因，包括FANCA、FANCF、FANCL、FANCD 2、BRCA 1和BRCA 2，是线粒体自噬所必需的。因此，FA途径的成员代表了以前未描述的一类在免疫和细胞器稳态中起作用的选择性自噬基因。这些发现对于理解FA和与FA基因突变相关的癌症的发病机制具有重要意义。
Fanconi anemia (FA) pathway genes are important tumor suppressors whose best-characterized function is repair of damaged nuclear DNA. Herein, we describe an essential role for FA genes in two forms of selective autophagy. Genetic deletion of Fancc blocks the autophagic clearance of viruses (virophagy) and increases susceptibility to lethal viral encephalitis. FANCC interacts with Parkin; is required in vitro and in vivo for clearance of damaged mitochondria; and decreases mitochondrial ROS production and inflammasome activation. The mitophagy function of FANCC is genetically distinct from its role in genomic DNA damage repair. Moreover, additional genes in the FA pathway, including FANCA, FANCF, FANCL, FANCD2, BRCA1 and BRCA2, are required for mitophagy. Thus, members of the FA pathway represent a previously undescribed class of selective autophagy genes that function in immunity and organellar homeostasis. These findings have implications for understanding the pathogenesis of FA and cancers associated with mutations in FA genes.