Crosstalk between the Secretory and Autophagy Pathways Regulates Autophagosome Formation

Abstract

The induction of autophagy by nutrient deprivation leads to a rapid increase in the formation of autophagosomes, unique organelles that replenish the cellular pool of nutrients by sequestering cytoplasmic material for degradation. The urgent need for membranes to form autophagosomes during starvation to maintain homeostasis leads to a dramatic rearrangement of intracellular membranes. Here we discuss recent findings that have begun to uncover how different parts of the secretory pathway directly and indirectly contribute to autophagosome formation during starvation.

Keywords: autophagosome formation; autophagy; secretory pathway.

Copyright © 2017 Elsevier Inc. All rights reserved.

Figures

Figure 1. Overview of autophagosome formation

The Atg proteins, which form 6 major groups, are recruited in a hierarchical manner to the PAS in yeast (top) or the omegasome in mammals (bottom). A double membrane track called the isolation membrane forms. The isolation membrane expands and then seals to form an autophagosome before it fuses with the vacuole in yeast or lysosome in mammals to release its contents for degradation.

Figure 2. COPII vesicles, tethers and other factors in autophagy

Formation of the COPII coat is initiated at ERES by the GEF Sec12. Sec16 at ERES facilitates coat assembly. Sec12 activates Sar1 and recruits the Sec23/Sec24 complex, which is followed by recruitment of the Sec13/Sec31 complex. After the coat has formed, Sar1 is released from the vesicle, and the coat remains on the vesicle to aid in intracellular targeting. CK1 phosphorylates Sec24, which enhances its interaction with Atg9. Atg9 vesicles are found at the growing edge of the isolation membrane that faces the ERES. Constitutive Atg9 trafficking requires the TRAPPIII complex, for transport from the early endosome to Golgi in yeast or endocytic to Golgi traffic in mammalian cells. Intra Golgi transport requires COG, which is needed for the trafficking of Atg9 vesicles to sites of autophagosome formation. TRAPPIII also binds the COPII coat and activates the GTPase Rab1, that participates in autophagosome formation. HOPS and Rab7 act after autophagosome formation in autophagosome-lysosome fusion.

Figure 3. The Golgi and endosomal system in autophagy

Left, in yeast, Atg9 traffics through the secretory pathway before it localizes to the early endosome. During starvation, TRAPPII traffics Atg9 from the early endosome to the late Golgi where Atg23 and Atg27 mediate the biogenesis of Atg9 vesicles that translocate to the PAS. Late endosome trafficking bypass pathways may also exist during starvation (dotted arrow). Right, at the plasma membrane (PM) in mammals, mATG9 and ATG16L1 are packaged into separate clathrin-coated vesicles. The interaction of mATG9 with RAPGAP TBC1D5 and AP2 facilitates its transport from the PM to the early endosome before it traffics to the recycling endosome, where it meets ATG16L1. ATG16L1 is recruited to the recycling endosome by SNX18/RAB11. The perinuclear recycling endosome is tubulated during starvation and ATG16L1 and mATG9 are subsequently recruited to the omegasome.