This entry represents short coiled-coil protein (SCOC). In human, SCOC is required for autophagosome formation during amino acid starvation. It forms a starvation-sensitive trimeric complex with UVRAG (UV radiation resistance associated gene) and FEZ1 and may regulate ULK1 and Beclin 1 complex activities [].
This entry includes Atg14 (autophagy-related protein 14) from budding yeasts, Vps38 from fission yeasts and their homologues, Atg14L/Bakor (beclin-1-associated autophagy-related key regulator) and UVRAG (UV irradiation resistance-associated gene), from animals. Atg14 is a hydrophilic protein with a coiled-coil motif at the N terminus region. Yeast cells with mutant Atg14 are defective not only in autophagy but also in sorting of carboxypeptidase Y (CPY), a vacuolar-soluble hydrolase, to the vacuole [].Barkor positively regulates autophagy through its interaction with Beclin-1, with decreased levels of autophagosome formation observed when Barkor expression is eliminated []. UVRAG is also a Beclin1 binding protein that positively stimulate starvation-induced autophagy []. Autophagy mediates the cellular response to nutrient deprivation, protein aggregation, and pathogen invasion in humans, and malfunction of autophagy has been implicated in multiple human diseases including cancer. Class III phosphatidylinositol 3-kinase (PI3-kinase) regulates multiple membrane trafficking. In yeast, two distinct PI3-kinase complexes are known: complex I (Vps34, Vps15, Vps30/Atg6, and Atg14) is involved in autophagy, andcomplex II (Vps34, Vps15, Vps30/Atg6, and Vps38) functions in the vacuolar protein sorting pathway []. In mammals, complex II is also involved in autophagy []. The mammalian counterparts of Vps34, Vps15, and Vps30/Atg6 are Vps34, p150, and Beclin 1, respectively, and UV irradiation resistance-associated gene (UVRAG) has been identified as identical to yeast Vps38 [].
This is the Rubicon homology domain (RH) characterised at the C-terminal of Rubicon, PLEKHM1 and Pacer, proteins that modulate late steps in autophagy [, ]. Rubicon (RUBCN) negatively regulates autophagy and endolysosomal trafficking by inhibiting PI3K complex II (PI3KC3-C2), which impairs autophagosome maturation process. Decrease in autophagy is associated to aging, then suppression of this process by Rubicon has been linked to decreased clearance of alpha-synuclein aggregates in neural tissues, impairment of liver cell homeostasis, and interstitial fibrosis in the kidney. PLEKHM1 is an adapter protein that regulates Rab7-dependent and HOPS complex-dependent fusion events in the endolysosomal system and couples autophagic and the endocytic trafficking pathways [, ], being involved in the suppression of endocytic transport rather than autophagosome maturation. Mutations in PLEKHM1 causes osteopetrosis []. On the other hand, Pacer (Protein associated with UVRAG as autophagy enhancer or Rubicon-like) positively regulates autophagy, promoting autophagosome maturation by facilitating the biogenesis of phosphatidylinositol 3-phosphate (PtdIns3P) in late steps of autophagy [, ]. It antagonizes RUBCN, thereby stimulating phosphatidylinositol 3-kinase activity of the PI3K/PI3KC3 complex []. Pacer is involved in neuronal autophagy, whose deficiency leads to impaired autophagy and accumulation of protein aggregates in ALS which correlates with cell death and vulnerability of motoneurons during ALS pathogenesis [].This domain contains nine conserved cysteines and one conserved histidine, which have been predicted to bind divalent zinc cations, being required for Rubicon and PLEKHM1 to interact with Rab7 [, ].
