Alternative titles; symbols
HGNC Approved Gene Symbol: AREL1
Cytogenetic location: 14q24.3 Genomic coordinates (GRCh38) : 14:74,661,256-74,713,080 (from NCBI)
AREL1 encodes an E3 ubiquitin ligase that limits the cellular response to apoptotic stimuli by ubiquitinating proapoptotic proteins following their release from mitochondria and directing their degradation via the proteasome (Kim et al., 2013).
By sequencing clones obtained from a size-fractionated human brain cDNA library, Nagase et al. (1997) cloned AREL1, which they designated KIAA0317. The deduced 823-amino acid protein had an apparent molecular mass of 97 kD by SDS-PAGE. RT-PCR detected low AREL1 expression in kidney, placenta, lung, liver, and testis, with little to no AREL1 expression in other tissues examined.
Kim et al. (2013) cloned mouse and human AREL1 based on their ability to confer resistance to p53 (TP53; 171190)-dependent apoptosis in transfected cells. The deduced 823-amino acid human protein contains an N-terminal filamin (see 300017)-like domain and a C-terminal HECT (homologous to E6AP (UBE3A; 601623) C terminus) domain. The HECT domains of mouse and human AREL1 share 97% amino acid identity. Northern blot analysis detected a 5.4-kb transcript in mouse brain, testis, heart, liver, lung, and kidney, with very low expression in skeletal muscle and spleen. Immunofluorescence analysis revealed that AREL1 localized to cytoplasmic puncta in human H1299 nonsmall lung carcinoma cells. It did not colocalize with nuclear or mitochondrial markers.
Kim et al. (2013) found that the isolated C-terminal HECT domain of human AREL1 (AREL1-HECT) showed autoubiquitination activity in the presence of a ubiquitin-activating E1 enzyme (see UBA1; 314370), the ubiquitin-conjugating E2 enzyme UBCH5A (UBE2D1; 602961), ubiquitin (191339), and ATP. Expression of AREL1-HECT inhibited apoptosis induced by various apoptotic stimuli in human cell lines. Conversely, knockdown of AREL1 elevated cell sensitivity to apoptotic stimuli. AREL1-HECT did not inhibit mitochondrial release of proapoptotic proteins, such as cytochrome c (123970), SMAC (DIABLO; 605219), HTRA2 (606441), and ARTS (SEPT4; 603696), but it inhibited downstream caspase (see CASP3; 600636) activation. AREL1 interacted with and ubiquitinated SMAC, HTRA2, and ARTS following their release from mitochondria, causing their proteasome-mediated degradation. AREL1-HECT did not associate with these apoptosis effectors in healthy cells, where they were sequestered in mitochondria. Kim et al. (2013) concluded that AREL1 is an antiapoptotic E3 ubiquitin ligase involved in the degradation of proapoptotic mitochondrial proteins.
Kim et al. (2013) determined that the AREL1 gene contains 20 exons and spans 51.9 kb.
By radiation hybrid analysis, Nagase et al. (1997) mapped the AREL1 gene to chromosome 14. Kim et al. (2013) mapped the AREL1 gene to chromosome 14q24.3 by genomic sequence analysis.
Kim, J., Kim, S. Y., Kim, B. M., Lee, H., Kim, I., Yun, J., Jo, Y., Oh, T., Jo, Y., Chae, H.-D., Shin, D. Y. Identification of a novel anti-apoptotic E3 ubiquitin ligase that ubiquitinates antagonists of inhibitor of apoptosis proteins SMAC, HtrA2, and ARTS. J. Biol. Chem. 288: 12014-12021, 2013. [PubMed: 23479728] [Full Text: https://doi.org/10.1074/jbc.M112.436113]
Nagase, T., Ishikawa, K., Nakajima, D., Ohira, M., Seki, N., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 4: 141-150, 1997. [PubMed: 9205841] [Full Text: https://doi.org/10.1093/dnares/4.2.141]