Pacer Mediates the Function of Class III PI3K and HOPS Complexes in Autophagosome Maturation by Engaging Stx17

Class III PI3-kinase (PI3KC3) is essential for autophagy initiation, but whether PI3KC3 participates in other steps of autophagy remains unknown. The HOPS complex mediates the fusion of intracellular vesicles to lysosome, but how HOPS specifically tethers autophagosome to lysosome remains elusive. H...

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Bibliographic Details
Published in:Molecular cell 2017-03, Vol.65 (6), p.1029-1043.e5
Main Authors: Cheng, Xiawei, Ma, Xiuling, Ding, Xianming, Li, Lin, Jiang, Xiao, Shen, Zhirong, Chen, She, Liu, Wei, Gong, Weihua, Sun, Qiming
Format: Article
Language:English
Subjects:
Autophagosomes - enzymology
Autophagy
Autophagy-Related Proteins - genetics
Autophagy-Related Proteins - metabolism
Beclin1
Class III Phosphatidylinositol 3-Kinases - metabolism
Endosomes - enzymology
Enzyme Activation
HEK293 Cells
HeLa Cells
Hep G2 Cells
Hepatocytes - enzymology
HOPS
Host-Pathogen Interactions
Humans
Intracellular Signaling Peptides and Proteins - genetics
Intracellular Signaling Peptides and Proteins - metabolism
Lipid Droplets - metabolism
Lysosomes - enzymology
Membrane Fusion
Pacer
PI3KC3
Protein Aggregates
Protein Binding
Protein Interaction Domains and Motifs
Qa-SNARE Proteins - genetics
Qa-SNARE Proteins - metabolism
RNA Interference
Rubicon
Salmonella typhimurium - growth & development
Signal Transduction
Stx-17
Time Factors
Transfection
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
UVRAG
Vesicular Transport Proteins - genetics
Vesicular Transport Proteins - metabolism
Vps34
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Summary:Class III PI3-kinase (PI3KC3) is essential for autophagy initiation, but whether PI3KC3 participates in other steps of autophagy remains unknown. The HOPS complex mediates the fusion of intracellular vesicles to lysosome, but how HOPS specifically tethers autophagosome to lysosome remains elusive. Here, we report Pacer (protein associated with UVRAG as autophagy enhancer) as a regulator of autophagy. Pacer localizes to autophagic structures and positively regulates autophagosome maturation. Mechanistically, Pacer antagonizes Rubicon to stimulate Vps34 kinase activity. Next, Pacer recruits PI3KC3 and HOPS complexes to the autophagosome for their site-specific activation by anchoring to the autophagosomal SNARE Stx17. Furthermore, Pacer is crucial for the degradation of hepatic lipid droplets, the suppression of Salmonella infection, and the clearance of protein aggregates. These results not only identify Pacer as a crucial multifunctional enhancer in autophagy but also uncover both the involvement of PI3KC3 and the mediators of HOPS’s specific tethering activity in autophagosome maturation. [Display omitted] •Pacer antagonizes Rubicon to activate the UVRAG-PI3KC3 subcomplex•Pacer recruits PI3KC3 and HOPS complex to promote autophagosome maturation•Pacer’s autophagosome association is mediated by Stx17 and phosphoinositides Cheng et al. demonstrate that Pacer antagonizes Rubicon to mediate the function of the UVRAG-PI3KC3 subcomplex in late steps of autophagy. Pacer recruits HOPS complex to regulate the fusion specificity of autophagosomes with late endosomes/lysosomes by anchoring to the autophagosomal Stx17.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2017.02.010