Entry - *619893 - KELCH-LIKE FAMILY, MEMBER 25; KLHL25 - OMIM

 
 
* 619893

KELCH-LIKE FAMILY, MEMBER 25; KLHL25


Alternative titles; symbols

KELCH-LIKE 25


HGNC Approved Gene Symbol: KLHL25

Cytogenetic location: 15q25.3     Genomic coordinates (GRCh38): 15:85,759,326-85,794,925 (from NCBI)


TEXT

▼ Description

KLHL25 forms a ubiquitin ligase complex with cullin-3 (CUL3; 613136) that targets ATP citrate lyase (ACLY; 108728) for ubiquitination and degradation (Zhang et al., 2016).


▼ Cloning and Expression

Dhanoa et al. (2013) reported that the human KLHL25 protein contains 589 amino acids and has a TB/POZ domain, a BACK domain, and 5 Kelch motifs.


▼ Mapping

Gross (2022) mapped the KLHL25 gene to chromosome 15q25.3 based on an alignment of the KLHL25 sequence (GenBank BC028100) with the genomic sequence (GRCh38).

▼ Gene Function

By coimmunoprecipitation and mass spectrometric analyses, Zhang et al. (2016) showed that ACLY interacted indirectly with CUL3 through KLHL25 to form a complex in human lung cancer H1299 cells. KLHL25 interacted directly with ACLY and functioned as a substrate adaptor to bridge ACLY to CUL3. CUL3-KLHL25 negatively regulated ACLY protein levels in cells through protein ubiquitination and degradation, and low CUL3 expression was associated with high ACLY expression in human lung cancer. Through negative regulation of ACLY, CUL3-KLHL25 reduced acetyl-CoA levels and inhibited lipid synthesis, which in turn contributed to the inhibitory effect of CUL3-KLHL25 on proliferation and anchorage-independent growth of lung cancer cells. In vivo analysis revealed that CUL3-KLHL25 inhibited growth of xenograft lung tumors in mice through negative regulation of ACLY.

Tian et al. (2021) found that Acly regulated differentiation of mouse inducible regulatory T cells (iTregs). Tgfb1 (190180) induced Acly downregulation through Cul3-Klhl25-mediated ubiquitination and degradation, which in turn facilitated iTreg differentiation. Analysis with human iTregs confirmed the conserved role of CUL3-KLHL25-mediated ACLY ubiquitination in iTreg differentiation. Analysis with a mouse inflammatory bowel disease (IBD; see 266600) model revealed an important role of Cul3-Klhl25-mediated Acly ubiquitination in colitis alleviation and in regulation of diarrhea.


▼ REFERENCES

  1. Dhanoa, B. S., Cogliati, T., Satish, A. G., Bruford, E. A., Friedman, J. S. Update on the Kelch-like (KLHL) gene family. Hum. Genomics 7: 13, 2013. Note: Electronic Article. [PubMed: 23676014, images, related citations] [Full Text]

  2. Gross, M. B. Personal Communication. Baltimore, Md. 5/25/2022.

  3. Tian, M., Hao, F., Jin, X., Sun, X., Jiang, Y., Wang, Y., Li, D., Chang, T., Zou, Y., Peng, P., Xia, C., Liu, J., Li, Y., Wang, P., Feng, Y., Wei, M. ACLY ubiquitination by CUL3-KLHL25 induces the reprogramming of fatty acid metabolism to facilitate iTreg differentiation. eLife 10: e62394, 2021. [PubMed: 34491895, images, related citations] [Full Text]

  4. Zhang, C., Liu, J., Huang, G., Zhao, Y., Yue, X., Wu, H., Li, J., Zhu, J., Shen, Z., Haffty, B. G., Hu, W., Feng, Z. Cullin3-KLHL25 ubiquitin ligase targets ACLY for degradation to inhibit lipid synthesis and tumor progression. Genes Dev. 30: 1956-1970, 2016. [PubMed: 27664236, images, related citations] [Full Text]


Contributors:
Matthew B. Gross - updated : 05/25/2022
Creation Date:
Bao Lige : 05/25/2022
Edit History:
mgross : 05/25/2022

* 619893

KELCH-LIKE FAMILY, MEMBER 25; KLHL25


Alternative titles; symbols

KELCH-LIKE 25


HGNC Approved Gene Symbol: KLHL25

Cytogenetic location: 15q25.3     Genomic coordinates (GRCh38): 15:85,759,326-85,794,925 (from NCBI)


TEXT

Description

KLHL25 forms a ubiquitin ligase complex with cullin-3 (CUL3; 613136) that targets ATP citrate lyase (ACLY; 108728) for ubiquitination and degradation (Zhang et al., 2016).


Cloning and Expression

Dhanoa et al. (2013) reported that the human KLHL25 protein contains 589 amino acids and has a TB/POZ domain, a BACK domain, and 5 Kelch motifs.


Mapping

Gross (2022) mapped the KLHL25 gene to chromosome 15q25.3 based on an alignment of the KLHL25 sequence (GenBank BC028100) with the genomic sequence (GRCh38).

Gene Function

By coimmunoprecipitation and mass spectrometric analyses, Zhang et al. (2016) showed that ACLY interacted indirectly with CUL3 through KLHL25 to form a complex in human lung cancer H1299 cells. KLHL25 interacted directly with ACLY and functioned as a substrate adaptor to bridge ACLY to CUL3. CUL3-KLHL25 negatively regulated ACLY protein levels in cells through protein ubiquitination and degradation, and low CUL3 expression was associated with high ACLY expression in human lung cancer. Through negative regulation of ACLY, CUL3-KLHL25 reduced acetyl-CoA levels and inhibited lipid synthesis, which in turn contributed to the inhibitory effect of CUL3-KLHL25 on proliferation and anchorage-independent growth of lung cancer cells. In vivo analysis revealed that CUL3-KLHL25 inhibited growth of xenograft lung tumors in mice through negative regulation of ACLY.

Tian et al. (2021) found that Acly regulated differentiation of mouse inducible regulatory T cells (iTregs). Tgfb1 (190180) induced Acly downregulation through Cul3-Klhl25-mediated ubiquitination and degradation, which in turn facilitated iTreg differentiation. Analysis with human iTregs confirmed the conserved role of CUL3-KLHL25-mediated ACLY ubiquitination in iTreg differentiation. Analysis with a mouse inflammatory bowel disease (IBD; see 266600) model revealed an important role of Cul3-Klhl25-mediated Acly ubiquitination in colitis alleviation and in regulation of diarrhea.


REFERENCES

  1. Dhanoa, B. S., Cogliati, T., Satish, A. G., Bruford, E. A., Friedman, J. S. Update on the Kelch-like (KLHL) gene family. Hum. Genomics 7: 13, 2013. Note: Electronic Article. [PubMed: 23676014] [Full Text: https://doi.org/10.1186/1479-7364-7-13]

  2. Gross, M. B. Personal Communication. Baltimore, Md. 5/25/2022.

  3. Tian, M., Hao, F., Jin, X., Sun, X., Jiang, Y., Wang, Y., Li, D., Chang, T., Zou, Y., Peng, P., Xia, C., Liu, J., Li, Y., Wang, P., Feng, Y., Wei, M. ACLY ubiquitination by CUL3-KLHL25 induces the reprogramming of fatty acid metabolism to facilitate iTreg differentiation. eLife 10: e62394, 2021. [PubMed: 34491895] [Full Text: https://doi.org/10.7554/eLife.62394]

  4. Zhang, C., Liu, J., Huang, G., Zhao, Y., Yue, X., Wu, H., Li, J., Zhu, J., Shen, Z., Haffty, B. G., Hu, W., Feng, Z. Cullin3-KLHL25 ubiquitin ligase targets ACLY for degradation to inhibit lipid synthesis and tumor progression. Genes Dev. 30: 1956-1970, 2016. [PubMed: 27664236] [Full Text: https://doi.org/10.1101/gad.283283.116]


Contributors:
Matthew B. Gross - updated : 05/25/2022

Creation Date:
Bao Lige : 05/25/2022

Edit History:
mgross : 05/25/2022



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OMIM® and Online Mendelian Inheritance in Man® are registered trademarks of the Johns Hopkins University.
Copyright® 1966-2024 Johns Hopkins University.

NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
OMIM® and Online Mendelian Inheritance in Man® are registered trademarks of the Johns Hopkins University.
Copyright® 1966-2024 Johns Hopkins University.
Printed: May 28, 2024