Journal
AUTOPHAGY
Volume 7, Issue 1, Pages 61-73Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/auto.7.1.14015
Keywords
Bif-1; Atg9 trafficking; Golgi fragmentation; membrane curvature; Beclin 1; UVRAG; class III PI3-kinase; autophagosome; starvation
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Funding
- James & Esther King Biomedical Research Program [08KN-15-17228]
- National Institutes of Health [CA82197, CA129682]
- American Cancer Society [RSG-05-244-01-CCG]
- Flight Attendant Medical Research Institute [FAMRI062463-CIA]
- NATIONAL CANCER INSTITUTE [R01CA129682, R01CA082197] Funding Source: NIH RePORTER
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Atg9 is a transmembrane protein essential for autophagy which cycles between the Golgi network, late endosomes and LC3-positive autophagosomes in mammalian cells during starvation through a mechanism that is dependent on ULK1 and requires the activity of the class III phosphatidylinositol-3-kinase (PI3KC3). In this study, we demonstrate that the N-BAR-containing protein, Bif-1, is required for Atg9 trafficking and the fission of Golgi membranes during the induction of autophagy. Upon starvation, Atg9-positive membranes undergo continuous tubulation and fragmentation to produce cytoplasmic punctate structures that are positive for Rab5, Atg16L and LC3. Loss of Bif-1 or inhibition of the PI3KC3 complex II suppresses starvation-induced fission of Golgi membranes and peripheral cytoplasmic redistribution of Atg9. Moreover, Bif-1 mutants, which lack the functional regions of the N-BAR domain that are responsible for membrane binding and/or bending activity, fail to restore the fission of Golgi membranes as well as the formation of Atg9 foci and autophagosomes in Bif-1-deficient cells starved of nutrients. Taken together, these findings suggest that Bif-1 acts as a critical regulator of Atg9 puncta formation presumably by mediating Golgi fission for autophagosome biogenesis during starvation.
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