Alternative titles; symbols
HGNC Approved Gene Symbol: USP21
Cytogenetic location: 1q23.3 Genomic coordinates (GRCh38) : 1:161,159,500-161,165,723 (from NCBI)
Ubiquitin (191339) is a highly conserved 76-amino acid protein involved in various cellular functions, including regulation of intracellular protein degradation, cell cycle progression, and signal transduction. Covalent conjugation of proteins by ubiquitin or ubiquitin-like molecules is an important posttranslational modification. Deubiquitinating enzymes are ubiquitin-specific thiol proteases that cleave either linear ubiquitin precursor proteins or ubiquitin conjugates. USP21 belongs to the ubiquitin-specific protease (USP) family of deubiquitinating enzymes, which are characterized by amino acid identity in 8 regions, including the cys box and the his box (summary by Gong et al., 2000).
By searching an EST database for USP-like sequences and screening an infant brain cDNA library, Smith and Southan (2000) identified cDNAs encoding USP21, which they called USP23. The deduced protein contains 566 amino acids. Northern blot analysis detected a 2.6-kb USP23 transcript in all tissues tested.
By searching an EST database for sequences encoding cys and his boxes, followed by PCR and 5-prime RACE of a placenta cDNA library, Gong et al. (2000) obtained a USP21 clone encoding 381 amino acids. The sequence contains all 8 motifs characteristic of USPs, including a conserved cysteine and 2 conserved histidines at the putative active site. Northern blot analysis detected variable expression of an approximately 2.2-kb transcript in all tissues examined, with highest expression in heart, pancreas, and skeletal muscle.
By assaying lysates of COS cells expressing USP21, Gong et al. (2000) showed that USP21 removed ubiquitin from ubiquitin-conjugated proteins. USP21 also removed NEDD8 (603171) from NEDD8 conjugates, but it had no effect on sentrin-1 (SUMO1; 601912) conjugates. Mutation of the putative active-site cysteine to alanine rendered USP21 inactive. Overexpression of USP21 in a human osteosarcoma cell line inhibited cell growth.
The core histone H2A (see 613499) is monoubiquitinated on a highly conserved residue (lys119), and ubiquitinated H2A functions in both gene activation and repression. Nakagawa et al. (2008) showed that ubiquitinated H2A was enriched in the promoter regions of repressed genes and in silenced chromatin during replication in regenerating mouse liver. Ubiquitinated H2A-specific repression was cancelled by Usp21.
Using an NF-kappa-B (see NFKB1; 164011)-dependent reporter, Xu et al. (2010) showed that USP21 significantly inhibited TNF-alpha (TNF; 191160)-induced NF-kappa-B reporter activity, whereas other USPs had little to no effect. Mutation of cys221 to ala in USP21 abolished the effect. Immunoprecipitation analysis revealed that USP21 interacted with RIP1 (RIPK1; 603453), a serine-threonine kinase whose polyubiquitination is essential for TNF-alpha-induced NF-kappa-B activation. Knockdown of USP21 in HeLa cells upregulated TNF-alpha-induced NF-kappa-B reporter activity, with concomitant elevation in TNF-alpha-induced RIP1 polyubiquitination, IKK (see 600664) and RELA (164014) phosphorylation, and I-kappa-B-alpha (NFKBIA; 164008) phosphorylation and ubiquitination. Knockdown of USP21 also elevated TNF-alpha-induced JNK (MAPK8; 601158) phosphorylation and IL6 (147620) mRNA and protein expression. Xu et al. (2010) concluded that USP21 terminates TNF-alpha-induced NF-kappa-B activation by deubiquitinating RIP1.
Smith and Southan (2000) stated that the USP21 gene had been mapped to chromosome 1q22 by radiation hybrid analysis. By genomic sequence analysis, Gong et al. (2000) mapped the USP21 gene to chromosome 1q21.
Gong, L., Kamitani, T., Millas, S., Yeh, E. T. H. Identification of a novel isopeptidase with dual specificity for ubiquitin- and NEDD8-conjugated proteins. J. Biol. Chem. 275: 14212-14216, 2000. [PubMed: 10799498] [Full Text: https://doi.org/10.1074/jbc.275.19.14212]
Nakagawa, T., Kajitani, T., Togo, S., Masuko, N., Ohdan, H., Hishikawa, Y., Koji, T., Matsuyama, T., Ikura, T., Muramatsu, M., Ito, T. Deubiquitylation of histone H2A activates transcriptional initiation via trans-histone cross-talk with H3K4 di- and trimethylation. Genes Dev. 22: 37-49, 2008. [PubMed: 18172164] [Full Text: https://doi.org/10.1101/gad.1609708]
Smith, T. S., Southan, C. Sequencing, tissue distribution and chromosomal assignment of a novel ubiquitin-specific protease USP23. Biochim. Biophys. Acta 1490: 184-188, 2000. [PubMed: 10786635] [Full Text: https://doi.org/10.1016/s0167-4781(99)00233-x]
Xu, G., Tan, X., Wang, H., Sun, W., Shi, Y., Burlingame, S., Gu, X., Cao, G., Zhang, T., Qin, J., Yang, J. Ubiquitin-specific peptidase 21 inhibits tumor necrosis factor alpha-induced nuclear factor kappa-B activation via binding to and deubiquitinating receptor-interacting protein 1. J. Biol. Chem. 285: 969-978, 2010. [PubMed: 19910467] [Full Text: https://doi.org/10.1074/jbc.M109.042689]