title: Fanconi Anemia Proteins Function in Mitophagy and Immunity.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Rhea
authors.initials: R
authors.lastname: Sumpter
authors.affiliation: Department of Internal Medicine, Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Shyam
authors.initials: S
authors.lastname: Sirasanagandla
authors.affiliation: Department of Internal Medicine, Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo 33006, Spain.
authors.forename: Álvaro F
authors.initials: ÁF
authors.lastname: Fernández
authors.affiliation: Department of Internal Medicine, Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Internal Medicine, Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Dong
authors.affiliation: Department of Internal Medicine, Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Franco
authors.affiliation: Department of Internal Medicine, Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Zhongju
authors.initials: Z
authors.lastname: Zou
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Christophe
authors.initials: C
authors.lastname: Marchal
authors.affiliation: Department of Internal Medicine, Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Ming Yeh
authors.initials: MY
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: D Wade
authors.initials: DW
authors.lastname: Clapp
authors.affiliation: Department of Pediatrics III, University of Duisburg-Essen, Essen 45122, Germany; Department of Otorhinolaryngology and Head/Neck Surgery, Heinrich Heine University, Düsseldorf 40225, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Hanenberg
authors.affiliation: Department of Internal Medicine, Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: beth.levine@utsouthwestern.edu.
authors.forename: Beth
authors.initials: B
authors.lastname: Levine
mesh_terms: D000818:Animals; D001343:Autophagy; D004622:Embryo, Mammalian / Q000166:cytology; D052218:Fanconi Anemia Complementation Group C Protein / Q000235:genetics / Q000378:metabolism*; D051856:Fanconi Anemia Complementation Group Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006367:HeLa Cells; D018259:Herpesvirus 1, Human / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D051379:Mice; D063306:Mitophagy; D017382:Reactive Oxygen Species / Q000378:metabolism; D012845:Sindbis Virus / Q000378:metabolism
chemical_list: C497652:Fancc protein, mouse; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D058847:Inflammasomes; D017382:Reactive Oxygen Species