UVRAG

This gene complements the ultraviolet sensitivity of xeroderma pigmentosum group C cells and encodes a protein with a C2 domain. The protein activates the Beclin1-PI(3)KC3 complex, promoting autophagy and suppressing the proliferation and tumorigenicity of human colon cancer cells. Chromosomal aberrations involving this gene are associated with left-right axis malformation and mutations in this gene have been associated with colon cancer. [provided by RefSeq, Jul 2008]
Diseases associated with UVRAG include Xeroderma Pigmentosum Group C and Cholecystolithiasis. Among its related pathways are Early SARS-CoV-2 Infection Events and Infectious disease. Gene Ontology (GO) annotations related to this gene include SH3 domain binding and SNARE binding.
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, 18552835, 20643123, 24056303, 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, 20643123, 24056303, 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, 20643123, 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, 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).
UV radiation resistance-associated gene
Late endosome {ECO:0000269 PubMed:18843052}
Lysosome {ECO:0000269 PubMed:18843052}
Cytoplasmic vesicle, autophagosome {ECO:0000269 PubMed:28306502}
Early endosome {ECO:0000269 PubMed:18552835, 18843052}
Endoplasmic reticulum {ECO:0000269 PubMed:24056303}
Midbody {ECO:0000269 PubMed:20643123}
Chromosome, centromere {ECO:0000269 PubMed:22542840}
Note: 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) {ECO:0000269 PubMed:24056303, 28306502}
lysosome 5
endosome 5
cytoskeleton 5
Quaternary structure:

Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex II (PI3KC3-C2) in which the core composed of the catalytic subunit PIK3C3, the regulatory subunit PIK3R4 and BECN1 is associated with UVRAG; in the complex interacts directly with BECN1.
PI3KC3-C2 can associate with further regulatory subunits such as RUBCN and probably SH3GLB1/Bif-1 (PubMed:16799551, 18843052, 19050071, 19270696, 20643123, 23878393, 24056303).
Interacts with SH3GLB1; UVRAG bridges the interaction to BECN1 indicative for an association with the PI3K complex PI3KC3-C2 (PubMed:17891140).
Interacts with RINT1.
Associates with the NRZ complex under basal conditions and dissociates from it under autophagy conditions to associate with the PI3K complex; these complex associations seem to be mutually exclusive (PubMed:24056303).
Interacts with VPS16; VPS11; VPS18; VPS33 (VPS33A or VPS33B) and VPS39; indicative for an association with a class C Vps tethering complex (possibly the HOPS complex) (PubMed:18552835, 25533187).
Interacts with RAB7A; RAB7A competes with UVRAG for RUBCN binding (PubMed:20974968, 25533187).
Interacts with STX7, VTI1B, STX8 (PubMed:24550300).
Interacts with PRKDC, XRCC6 and XRCC5; indicative for an association with the DNA-dependent protein kinase complex DNA-PK.
Interacts with CEP63 (PubMed:22542840).
Directly interacts with FEZ1 and SCOC; the interaction with SCOC is reduced by amino acid starvation, but the complex is stabilized in the presence of FEZ1 (PubMed:22354037).
Interacts with BECN1P1/BECN2 (PubMed:23954414).
Interacts with SLAMF1 (PubMed:22493499).
Interacts with RUBCNL/PACER; promoting targeting of UVRAG to autophagosome (PubMed:28306502).
Interacts with WNK1 (PubMed:27911840).