The Golgi apparatus is a central intracellular membrane-bound organelle with key functions in trafficking, processing, and sorting of newly synthesized membrane and secretory proteins and lipids. To best perform these functions, Golgi membranes form a unique stacked structure. The Golgi structure is dynamic but tightly regulated; it undergoes rapid disassembly and reassembly during the cell cycle of mammalian cells and is disrupted under certain stress and pathological conditions. In the past decade, significant amount of effort has been made to reveal the molecular mechanisms that regulate the Golgi membrane architecture and function. Here we review the major discoveries in the mechanisms of Golgi structure formation, regulation, and alteration in relation to its functions in physiological and pathological conditions to further our understanding of Golgi structure and function in health and diseases.

It has been indicated that the Golgi apparatus contributes to autophagy, but how it is involved in autophagosome formation and maturation is not well understood. Here we show that amino acid starvation causes trans-Golgi derived membrane fragments to colocalize with autophagosomes. Depletion of the Golgi stacking protein GORASP2/GRASP55, but not GORASP1/GRASP65, increases both MAP1LC3 (LC3)-II and SQSTM1/p62 levels. We demonstrate that GORASP2 facilitates autophagosome-lysosome fusion by physically linking autophagosomes and lysosomes through the interactions with LC3 on autophagosomes and LAMP2 on late endosomes/lysosomes. Furthermore, we provide evidence that GORASP2 interacts with BECN1 to facilitate the assembly and membrane association of the phosphatidylinositol 3-kinase (PtdIns3K) UVRAG complex. These findings indicate that GORASP2 plays an important role in autophagosome maturation during amino acid starvation.

The Golgi stacking proteins, GRASP55 and GRASP65, are best known for their roles in Golgi structure formation. These peripheral Golgi proteins form trans -oligomers that hold the flat cisternal membranes into stacks. Depletion of both GRASP proteins in cells disrupts the Golgi stack structure, increases protein trafficking, but impairs accurate glycosylation, and sorting. Golgi unstacking by GRASPs depletion also reduces cell adhesion and migration in an integrin-dependent manner. In addition to Golgi structure formation and regulation of cellular activities, GRASPs, in particular GRASP55, have recently drawn attention in their roles in autophagy, and unconventional secretion. In autophagy, GRASP55 senses the energy level by O-GlcNAcylation, which regulates GRASP55 translocation from the Golgi to the autophagosome-lysosome interface, where it interacts with LC3 and LAMP2 to facilitate autophagosome-lysosome fusion. This newly discovered function of GRASP55 in autophagy may help explain its role in the stress-induced, autophagosome-dependent unconventional secretion. In this review, we summarize the emerging functions of the GRASP proteins, focusing on their roles in cell adhesion and migration, autophagy, unconventional secretion, as well as on novel GRASP-interacting proteins.

The Golgi apparatus is a membrane-bound organelle that serves as the center for trafficking and processing of proteins and lipids. To perform these functions, the Golgi forms a multilayer stacked structure held by GRASP55 and GRASP65 trans-oligomers and perhaps their binding partners. Depletion of GRASP proteins disrupts Golgi stack formation and impairs critical functions of the Golgi, such as accurate protein glycosylation and sorting. However, how Golgi destruction affects other cellular activities is so far unknown. Here, we report that depletion of GRASP proteins reduces cell attachment and migration. Interestingly, GRASP depletion reduces the protein level of α5β1 integrin, the major cell adhesion molecule at the surface of HeLa and MDA-MB-231 cells, due to decreased integrin protein synthesis. GRASP depletion also increases cell growth and total protein synthesis. These new findings enrich our understanding on the role of the Golgi in cell physiology and provide a potential target for treating protein-trafficking disorders.

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