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.

The autophagy pathway is an essential component of host defense against viral infection, orchestrating pathogen degradation (xenophagy), innate immune signaling, and certain aspects of adaptive immunity. Single autophagy proteins or cassettes of the core autophagy machinery can also function as antiviral factors independently of the canonical autophagy pathway. Moreover, to survive and propagate within the host, viruses have evolved a variety of strategies to evade autophagic attack and manipulate the autophagy machinery for their own benefit. This review summarizes recent advances in understanding the antiviral and proviral roles of autophagy and previously unappreciated autophagy-independent functions of autophagy-related genes.

Summary The molecular mechanism of autophagy and its relationship to other lysosomal degradation pathways remain incompletely understood. Here, we identified a previously uncharacterized mammalian-specific protein, Beclin 2, which like Beclin 1, functions in autophagy and interacts with class III PI3K complex components and Bcl-2. However, Beclin 2, but not Beclin 1, functions in an additional lysosomal degradation pathway. Beclin 2 is required for ligand-induced endolysosomal degradation of several G protein-coupled receptors (GPCRs) through its interaction with GASP1. Beclin 2 homozygous knockout mice have decreased embryonic viability, and heterozygous knockout mice have defective autophagy, increased levels of brain cannabinoid 1 receptor, elevated food intake, and obesity and insulin resistance. Our findings identify Beclin 2 as a novel converging regulator of autophagy and GPCR turnover, and highlight the functional and mechanistic diversity of Beclin family members in autophagy, endolysosomal trafficking and metabolism.

The Beclin family, including yeast Atg6 (autophagy related gene 6), its orthologs in higher eukaryotic species, and the more recently characterized mammalian-specific Beclin 2, are essential molecules in autophagy and other membrane-trafficking events. Extensive studies of Beclin orthologs have provided considerable insights into the regulation of autophagy, the diverse roles of autophagy in physiology and disease, and potential new strategies to modulate autophagy in a variety of clinical diseases. In this review we discuss the functions of Beclin 1 orthologs, the regulation of such functions by diverse cellular signaling pathways, and the effects of such regulation on downstream cellular processes including tumor suppression and metabolism. These findings suggest that Beclin orthologs serve as crucial molecules that integrate diverse environmental signals with membrane trafficking events to ensure optimal responses of the cell to stressful stimuli.

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