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. 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.
['Cheng|Xiawei|X|', 'Ma|Xiuling|X|', 'Ding|Xianming|X|', 'Li|Lin|L|', 'Jiang|Xiao|X|', 'Shen|Zhirong|Z|', 'Chen|She|S|', 'Liu|Wei|W|', 'Gong|Weihua|W|', 'Sun|Qiming|Q|']
D000071182:Autophagosomes D001343:Autophagy D000071183:Autophagy-Related Proteins D058546:Class III Phosphatidylinositol 3-Kinases D011992:Endosomes D004789:Enzyme Activation D057809:HEK293 Cells D006367:HeLa Cells D056945:Hep G2 Cells D022781:Hepatocytes D054884:Host-Pathogen Interactions D006801:Humans D047908:Intracellular Signaling Peptides and Proteins D066292:Lipid Droplets D008247:Lysosomes D008561:Membrane Fusion D066329:Protein Aggregates D011485:Protein Binding D054730:Protein Interaction Domains and Motifs D050765:Qa-SNARE Proteins D034622:RNA Interference D012486:Salmonella typhimurium D015398:Signal Transduction D013997:Time Factors D014162:Transfection D025521:Tumor Suppressor Proteins D033921:Vesicular Transport Proteins
Pacer HOPS PI3KC3 UVRAG Rubicon Vps34 Beclin1 Stx-17