TY - JOUR
T1 - Fanconi Anemia Proteins Function in Mitophagy and Immunity
AU - Sumpter, Rhea
AU - Sirasanagandla, Shyam
AU - Fernández, Álvaro F.
AU - Wei, Yongjie
AU - Dong, Xiaonan
AU - Franco, Luis
AU - Zou, Zhongju
AU - Marchal, Christophe
AU - Lee, Ming Yeh
AU - Clapp, D. Wade
AU - Hanenberg, Helmut
AU - Levine, Beth
N1 - Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/5/5
Y1 - 2016/5/5
N2 - Summary 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.
AB - Summary 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.
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U2 - 10.1016/j.cell.2016.04.006
DO - 10.1016/j.cell.2016.04.006
M3 - Article
C2 - 27133164
AN - SCOPUS:84964587158
SN - 0092-8674
VL - 165
SP - 867
EP - 881
JO - Cell
JF - Cell
IS - 4
ER -