Fanconi Anemia Proteins Function in Mitophagy and Immunity

• Published in: Cell Vol. 165; no. 4; pp. 867 - 881
• Main Authors: Sumpter, Rhea, Sirasanagandla, Shyam, Fernández, Álvaro F., Wei, Yongjie, Dong, Xiaonan, Franco, Luis, Zou, Zhongju, Marchal, Christophe, Lee, Ming Yeh, Clapp, D. Wade, Hanenberg, Helmut, Levine, Beth
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.05.2016
• Subjects: Animals; Autophagy; Embryo, Mammalian - cytology; Fanconi Anemia Complementation Group C Protein - genetics; Fanconi Anemia Complementation Group C Protein - metabolism; Fanconi Anemia Complementation Group Proteins - metabolism; Fibroblasts - metabolism; HeLa Cells; Herpesvirus 1, Human - metabolism; Humans; Inflammasomes - metabolism; Mice; Mitochondrial Degradation; Reactive Oxygen Species - metabolism; Sindbis Virus - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2016.04.006

Fanconi anemia (FA) pathway genes are important tumor suppressors whose best-characterized function is repair of damaged nuclear DNA. Here, 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. Fanconi anemia complementation group C (FANCC) protein interacts with Parkin, is required in vitro and in vivo for clearance of damaged mitochondria, and decreases mitochondrial reactive oxygen species (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. [Display omitted] •FANCC functions in two forms of selective autophagy: virophagy and mitophagy•Fancc is required in mice for antiviral host defense and mitochondrial homeostasis•Fancc suppresses inflammasome activation by removing damaged mitochondria•Multiple proteins in the Fanconi anemia pathway are required for mitophagy Fanconi anemia (FA) pathway genes are involved in genomic DNA repair, and mutations in FA genes are associated with bone marrow failure and cancer. Here, we show that FA genes (including BRCA1/FANCS and BRCA2/FANCD1) are required for selective autophagy, which removes unwanted cytoplasmic contents. FA gene deficiency results in impaired virophagy and antiviral host defense, decreased Parkin-mediated mitophagy, and increased mitochondrial ROS-dependent inflammasome activation. Loss of FA-gene-mediated selective autophagy may contribute to the pathophysiology of FA-gene-associated diseases.