Golgi-resident Rab2 GTPase Regulates Autophagosome Biogenesis And Maturation In Bulk And Selective Autophagy

Autophagy is a highly conserved lysosomal-mediated intracellular degradation pathway that plays a crucial role in development and homeostasis.Disfunction of autophagy is associated with variety of human diseases,such as neuron degeneration diseases,diabetes,infectious diseases,immune system diseases and cancer.In the process of autophagy,intracellular degradation substrates,including protein aggregates,damaged or redundant organelles,invading pathogenic microorganisms and other autophagic substrates are engulfed by autophagosomes and then degrade with lysosomes.Eventually,nutrients such as amino acids are regenerated.Although researchers pay more attention to autophagy and make great progress in understanding its mechanism,there still remains large unknown especially in regulation of biogenesis and maturation of autophagosome.The Golgi apparatus is an organelle with many important physiological functions consisting of many flat membrane vesicles and vesicles of different sizes.Golgi involved in the secretion,lysosome maturation,cell cycle,autophagy and other important physiological processes.Multiple sources,including the Golgi apparatus,contribute membrane and protein machineries to autophagy.However,the underlying molecular mechanisms remain largely unknown.The Rab family of small GTPase(Rab GTPase)works as switch molecules in various membrane transport processes.Therefore,Rabs play an extremely important role in the organelle interaction network.Currently,there are more than 60 Rabs found in mammalian,which are important for precise transportation of intracellular substances.Rab2 is a member of the Rab family and exists in the pre-Golgi apparatus.Rab2 is responsible for the membrane transport of Golgi to the endoplasmic reticulum.It is unknown whether Rab2 play roles in autophagy.Here,we report that a Rab2 signaling cascade connects the Golgi network to both nonselective and selective autophagy pathways by delivering membrane and by sequentially engaging distinct autophagy machineries.In unstressed cells,GM130 interacts with Rab2 on the Golgi apparatus to reserve a population of Rab2+Atg9+vesicles that are destined for autophagy initiation.Autophagy stimuli liberate Rab2+Atg9+vesicles from GM130-restriction to recruit and activate ULK1,which dictates the incorporation of the Rab2+Atg9+ULK1+vesicles into pre-autophagosomal structures.During the process of autophagosome formation,Rab2 further switches to interact with autophagosomal Pacer and Stx17 to stabilize its own residency on autophagosomes by preventing GPI2-mediated membrane extraction.Next,the complex containing Pacer,Stx17 and Rab2 recruits HOPS complex to facilitate the autophagosome maturation by specifying the tethering of autophagosomes with late endosomes or lysosomes.Unexpectedly,Rab2 directly binds to p62 to facilitate p62-mediated selective autophagy in parallel to its function in bulk autophagy.Together,our study identifies a multivalent signaling pathway in bulk and selective autophagy regulation,and provides mechanistic insights into how the Golgi apparatus contributes to the formation of different autophagic structures upon cellular demand.