UVRAG
Function
Versatile protein that is involved in regulation of different cellular pathways implicated in membrane trafficking. Involved in regulation of the COPI-dependent retrograde transport from Golgi and the endoplasmic reticulum by associating with the NRZ complex; the function is dependent on its binding to phosphatidylinositol 3-phosphate (PtdIns(3)P) (PubMed:16799551, PubMed:18552835, PubMed:20643123, PubMed:24056303, PubMed:28306502). During autophagy acts as a regulatory subunit of the alternative PI3K complex II (PI3KC3-C2) that mediates formation of phosphatidylinositol 3-phosphate and is believed to be involved in maturation of autophagosomes and endocytosis. Activates lipid kinase activity of PIK3C3 (PubMed:16799551, PubMed:20643123, PubMed:24056303, PubMed:28306502). Involved in the regulation of degradative endocytic trafficking and cytokinesis, and in regulation of ATG9A transport from the Golgi to the autophagosome; the functions seems to implicate its association with PI3KC3-C2 (PubMed:16799551, PubMed:20643123, PubMed:24056303). Involved in maturation of autophagosomes and degradative endocytic trafficking independently of BECN1 but depending on its association with a class C Vps complex (possibly the HOPS complex); the association is also proposed to promote autophagosome recruitment and activation of Rab7 and endosome-endosome fusion events (PubMed:18552835, PubMed:28306502). Enhances class C Vps complex (possibly HOPS complex) association with a SNARE complex and promotes fusogenic SNARE complex formation during late endocytic membrane fusion (PubMed:24550300). In case of negative-strand RNA virus infection is required for efficient virus entry, promotes endocytic transport of virions and is implicated in a VAMP8-specific fusogenic SNARE complex assembly (PubMed:24550300).
Involved in maintaining chromosomal stability. Promotes DNA double-strand break (DSB) repair by association with DNA-dependent protein kinase complex DNA-PK and activating it in non-homologous end joining (NHEJ) (PubMed:22542840). Required for centrosome stability and proper chromosome segregation (PubMed:22542840).
Involvement in disease
A chromosomal aberration involving UVRAG has been observed in a patient with heterotaxy (left-right axis malformation). Inversion Inv(11)(q13.5;q25).
Post-translational modifications
Phosphorylated at Ser-498 by MTOR under basal conditions; increases the interaction with RUBCN implicated in inhibitory effect of RUBCN on PI3KC3 and decreases interaction with RAB7,A and VPS16 and VPS39 (indicative for a class C Vps complex, possibly the HOPS complex) (PubMed:25533187).
Tissue Specificity
Highly expressed in brain, lung, kidney and liver.
Cellular localization
- Late endosome
- Lysosome
- Cytoplasmic vesicle
- Autophagosome
- Early endosome
- Endoplasmic reticulum
- Midbody
- Chromosome
- Centromere
- Colocalizes with RAB9-positive compartments involved in retrograde transport from late endosomes to trans-Golgi network. Colocalization with early endosomes is only partial (PubMed:24056303). Recruited to autophagosome following interaction with RUBCNL/PACER (PubMed:28306502).
Alternative names
UV radiation resistance-associated gene protein, p63, UVRAG