ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes

Jiajie Diao, Rong Liu, Yueguang Rong, Minglei Zhao, Jing Zhang, Ying Lai, Qiangjun Zhou, Livia M. Wilz, Jianxu Li, Sandro Vivona, Richard A. Pfuetzner, Axel T. Brunger, Qing Zhong

Research output: Contribution to journalArticle

230 Scopus citations

Abstract

Autophagy, an important catabolic pathway implicated in a broad spectrum of human diseases, begins by forming double membrane autophagosomes that engulf cytosolic cargo and ends by fusing autophagosomes with lysosomes for degradation. Membrane fusion activity is required for early biogenesis of autophagosomes and late degradation in lysosomes. However, the key regulatory mechanisms of autophagic membrane tethering and fusion remain largely unknown. Here we report that ATG14 (also known as beclin-1-associated autophagy-related key regulator (Barkor) or ATG14L), an essential autophagy-specific regulator of the class III phosphatidylinositol 3-kinase complex, promotes membrane tethering of protein-free liposomes, and enhances hemifusion and full fusion of proteoliposomes reconstituted with the target (t)-SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) syntaxin 17 (STX17) and SNAP29, and the vesicle (v)-SNARE VAMP8 (vesicle-associated membrane protein 8). ATG14 binds to the SNARE core domain of STX17 through its coiled-coil domain, and stabilizes the STX17-SNAP29 binary t-SNARE complex on autophagosomes. The STX17 binding, membrane tethering and fusion-enhancing activities of ATG14 require its homo-oligomerization by cysteine repeats. In ATG14 homo-oligomerization-defective cells, autophagosomes still efficiently form but their fusion with endolysosomes is blocked. Recombinant ATG14 homo-oligomerization mutants also completely lose their ability to promote membrane tethering and to enhance SNARE-mediated fusion in vitro. Taken together, our data suggest an autophagy-specific membrane fusion mechanism in which oligomeric ATG14 directly binds to STX17-SNAP29 binary t-SNARE complex on autophagosomes and primes it for VAMP8 interaction to promote autophagosome-endolysosome fusion.

Original languageEnglish (US)
Pages (from-to)563-566
Number of pages4
JournalNature
Volume520
Issue number7548
DOIs
StatePublished - Apr 23 2015

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    Diao, J., Liu, R., Rong, Y., Zhao, M., Zhang, J., Lai, Y., Zhou, Q., Wilz, L. M., Li, J., Vivona, S., Pfuetzner, R. A., Brunger, A. T., & Zhong, Q. (2015). ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes. Nature, 520(7548), 563-566. https://doi.org/10.1038/nature14147