Golgi inCOGnito: From vesicle tethering to human disease

Abstract

The Conserved Oligomeric Golgi (COG) complex, a multi-subunit vesicle tethering complex of the CATCHR (Complexes Associated with Tethering Containing Helical Rods) family, controls several aspects of cellular homeostasis by orchestrating retrograde vesicle traffic within the Golgi. The COG complex interacts with all key players regulating intra-Golgi trafficking, namely SNAREs, SNARE-interacting proteins, Rabs, coiled-coil tethers, and vesicular coats. In cells, COG deficiencies result in the accumulation of non-tethered COG-complex dependent (CCD) vesicles, dramatic morphological and functional abnormalities of the Golgi and endosomes, severe defects in N- and O- glycosylation, Golgi retrograde trafficking, sorting and protein secretion. In humans, COG mutations lead to severe multi-systemic diseases known as COG-Congenital Disorders of Glycosylation (COG-CDG). In this report, we review the current knowledge of the COG complex and analyze COG-related trafficking and glycosylation defects in COG-CDG patients.

Whole genome CRISPR screens identify LRRK2-regulated endocytosis as a major mechanism for extracellular tau uptake by human neurons

“…Tau uptake has previously been shown to be mediated by plasma membrane heparan sulfate proteoglycans 6 , and mutations in COG complex components result in congenital disorders of glycosylation in humans that have a wide spectrum of neurodevelopmental pathologies 21 . Two other genes required for aggregated tau uptake, B3GALNT1 and B3GNTL1, encode glycosyltransferases 35 .…”

“…Similarly, genes encoding vATPase subunits were required for aggregated tau uptake (ATP6V0E2, ATP6V0D1, ATP6V0A1), as were autophagy genes such as GABARAPL1 and UVRAG. Several genes encoding proteins involved in intracellular vesicular trafficking were also required for aggregated tau uptake, including the AP-1 and AP-3 complexes (AP1G1, AP3S1), and the COG complex that regulates retrograde trafficking within the Golgi 21 (four of the eight COG subunits: 1, 4, 7 & 8).…”

The Golgi-associated retrograde protein (GARP) complex plays an essential role in the maintenance of the Golgi glycosylation machinery

“…The Golgi complex plays a central role in the processing, packaging and sorting of secretory and transmembrane proteins in eukaryotic cells (1) (2). Although the Golgi complex was discovered more than 120 years ago, the molecular mechanisms of intra-Golgi trafficking and Golgi maintenance are not entirely understood (2).…”

“…However, the exact trafficking itineraries and molecular machinery involved in the delivery of these enzymes to their corresponding Golgi cisternae are poorly understood. Potential components of this machinery are coat proteins, small GTPases, vesicle tethers, and SNAREs implicated in inter-compartmental cargo transport in both anterograde and retrograde pathways (7) (1) (8). Each Golgi cisterna contains different carbohydrate-modifying enzymes.…”

“…The conserved oligomeric Golgi (COG) complex is the major Golgi vesicle tethering complex responsible for the maintenance of the Golgi glycosylation machinery (1) (10). Several lines of evidence indicate that COG and another vesicle tethering complex, the Golgi-Associated Retrograde Protein (GARP) complex, are functionally interconnected (11) (12).…”