VPS34

By Christina Towers, PhD

By Christina Towers, PhD

By Christina Towers, PhD

By Christina Towers, PhD.

By Christina Towers, PhD.

UV resistance-associated gene (UVRAG) is a tumor suppressor that is commonly mutated in colon and breast cancer. While UVRAG was discovered for its ability to complement UV sensitivity in xeroderma pigmentosum cells, its main functions are in autophagy, endocytosis, and apoptosis. During autophagy UVRAG interacts with Beclin 1 to promote autophagosome formation. UVRAG can also interact with VPS16 to recruit membrane fusion machinery to mediate autophagosome maturation.

VPS34, vacuolar protein sorting 34, is the only identified Class III phosphoinositide-3 kinase (PI3K) in mammals and is ubiquitously expressed in all eukaryotic cells. VPS34 is a 100 kDa protein responsible for phosphorylating phosphatidylinositol to produce phosphatidylinositol 3-phosphate (PI3P). PI3P is an important intermediate in the development of the double-membraned autophagosome during autophagy, indicating a role for VPS34 in autophagy initiation. PI3P allows VPS34 to form complexes with ATG14L during the elongation of the autophagosome membrane.

Autophagy is an important cellular process involved in degradation and recycling of cellular macromolecules in response to stress or starvation. Autophagy is carried out in four main phases: phagophore nucleation, autophagosome elongation, docking and fusion with a lysosome, and vesicle breakdown and degradation. ULK1, also known as UNC51-like autophagy activating kinase 1, is a 112 kDa protein with serine-threonine kinase activity. ULK1 is one of two mammalian homologues of the yeast ATG1 kinase, known for its role in autophagy initiation (1).

Membrane fusion is an essential step during the trafficking of endosomes and vesicles throughout the cell. Membrane fusion events are facilitated by multisubunit tethering complexes (MTC) including CORVET and HOPS. These complexes interact with Rab GTPases and SNARE proteins to promote the fusion of endosomes and lysosomes (1). In yeast VPS41 is a component of the HOPS complex that is needed for transport of endosomes and Golgi-derived vesicles to the vacuole. The choice between these two substrates is facilitated by the phosphorylation of VPS1 by Yck3 (2). Carbrera et al.