Alternative titles; symbols
HGNC Approved Gene Symbol: KLHDC10
Cytogenetic location: 7q32.2 Genomic coordinates (GRCh38): 7:130,070,534-130,135,705 (from NCBI)
By virtue of its interaction with proteins of varied function, KLHDC10 is predicted to influence several intracellular pathways, including oxidative stress-induced apoptosis (Sekine et al., 2012).
By sequencing clones from a KG-1 human immature myeloid cell line cDNA library, Nagase et al. (1996) obtained a partial KLHDC10 clone, which they designated KIAA0265. The deduced protein contained 401 amino acids. Northern blot analysis detected moderate KLHDC10 expression in skeletal muscle, with lower expression in all other tissues and cell lines examined.
By searching a human database for proteins similar to Drosophila Slim, Sekine et al. (2012) identified KLHDC10. The deduced 442-amino acid protein contains a large central kelch repeat domain, followed by putative Cul2 and BC boxes. The kelch repeat domain is predicted to form a 6-bladed beta propeller structure. The Cul2 box is predicted to bind cullin-2 (CUL2; 603135) of the CUL2 ubiquitin ligase complex, and the BC box is predicted to bind the CUL2 adaptor proteins elongin B (TCEB2; 600787) and elongin C (TCEB1; 600788). Epitope-tagged KLHDC10 localized predominantly to the nucleus of transfected HEK203 cells.
Similar to their results with Drosophila Slim, Sekine et al. (2012) found that human KLHDC10 was involved in activation of apoptosis signal-regulating kinase-1 (ASK1; 602448) via its kelch repeat domain. The activation of ASK1 by reactive oxygen species (ROS) is involved in oxidative stress-mediated cell death. Overexpression of KLHDC10 and ASK1 in HEK293 cells resulted in activation of ASK1 and downstream effectors JNK (see MAPK8, 601158) and p38 (MAPK14; 600289). Immunoprecipitation of HEK293 cells revealed that KLHDC10 interacted with PP5 (PPP5C, 600658), a protein phosphatase known to inactivate ASK1 via dephosphorylation of an essential phosphothreonine. KLHDC10 interacted directly with the phosphatase domain of PP5. Both H2O2 and TNF-alpha (TNF; 191160) increased the binding between KLHDC10 and PP5. Knockdown of Klhdc10 in Neuro2A cells reduced H2O2-dependent activation of Ask1 and p38, and suppressed H2O2-induced cell death. Immunoprecipitation analysis of mouse Neuro2A neuroblastoma cells revealed that endogenous Klhdc10 also interacted with Cul2, elongin B, and elongin C, and that the interaction requires a functional C-terminal BC box of Klhdc10. Knockdown of Cul2 increased the protein level of Klhdc10.
By radiation hybrid analysis, Nagase et al. (1996) mapped the KLHDC10 gene to chromosome 7.
Hartz (2013) mapped the KLHDC10 gene to chromosome 7q32.2 based on an alignment of the KLHDC10 sequence (GenBank D87454) with the genomic sequence (GRCh37).
Hartz, P. A. Personal Communication. Baltimore, Md. 3/26/2013.
Nagase, T., Seki, N., Ishikawa, K., Ohira, M., Kawarabayasi, Y., Ohara, O., Tanaka, A., Kotani, H., Miyajima, N., Nomura, N. Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain. DNA Res. 3: 321-329, 1996. [PubMed: 9039502] [Full Text: https://doi.org/10.1093/dnares/3.5.321]
Sekine, Y., Hatanaka, R., Watanabe, T., Sono, N., Iemura, S., Natsume, T., Kuranaga, E., Miura, M., Takeda, K., Ichijo, H. The Kelch repeat protein KLHDC10 regulates oxidative stress-induced ASK1 activation by suppressing PP5. Molec. Cell 48: 692-704, 2012. [PubMed: 23102700] [Full Text: https://doi.org/10.1016/j.molcel.2012.09.018]