Alternative titles; symbols
HGNC Approved Gene Symbol: PSMC3
Cytogenetic location: 11p11.2 Genomic coordinates (GRCh38): 11:47,418,775-47,426,439 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p11.2 | ?Deafness, cataract, impaired intellectual development, and polyneuropathy | 619354 | Autosomal recessive | 3 |
The human immunodeficiency virus-1 (HIV-1) protein Tat is a potent activator of virus gene expression and replication. Nelbock et al. (1990) used biotinylated Tat as a probe to screen a lambda-gt11 fusion protein library, thereby cloning a cDNA encoding a protein that interacts with Tat. Expression of this protein, designated Tat-binding protein-1, was observed in a variety of cell lines, with expression being highest in human cells. TBP1 was localized predominantly in the nucleus, which is consistent with the nuclear localization of Tat. In cotransfection experiments, expression of TBP1 was able to suppress Tat-mediated transactivation specifically. Nelbock et al. (1990) recommended their strategy for direct identification and cloning of genes encoding proteins that associate with other proteins to modulate their activity in a positive or negative fashion. Ohana et al. (1993) suggested that TBP1 is involved in Tat-mediated transcriptional activation.
By PCR amplification of a partial PSMC3 sequence, Hoyle et al. (1997) demonstrated that the PSMC3 gene is located on chromosome 11. By fluorescence in situ hybridization (FISH), the assignment was regionalized to 11p13-p12. Tanahashi et al. (1998) mapped the PSMC3 gene to 11p11.2 by FISH. By interspecific backcross analysis, Sakao et al. (2000) mapped the mouse Psmc3 gene to chromosome 2.
Ubiquitinated proteins are degraded by a 26S ATP-dependent protease. The protease is composed of a 20S catalytic proteasome and 2 PA700 regulatory modules (see PSMC1; 602706). DeMartino et al. (1996) identified a protein complex that enhances PA700 activation of the proteasome. They found that 2 proteins, p42 (PSMC6; 602708) and p50 (PSMC3), are components of both this complex and PA700. By protein sequence analysis, DeMartino et al. (1996) determined that p50 and TBP1 are identical.
Hoyle et al. (1997) stated that the PSMC3 gene encodes a protein with 1 AAA (ATPases associated with diverse cellular activities) domain (see PSMC5; 601681) toward the C terminus.
Corn et al. (2003) established that pVHL (608537), the protein that is mutant in von Hippel-Lindau syndrome (193300), binds to TBP1. TBP1 associates with the beta-domain of pVHL and complexes with pVHL and hypoxia-inducible transcription factor HIF1A (603348) in vivo. Overexpression of TBP1 promotes degradation of HIF1A in a pVHL-dependent manner that requires the ATPase domain of TBP1. Several distinct mutations in exon 2 of the VHL gene disrupt binding of pVHL to TBP1. A pVHL mutant containing an exon 2 missense substitution coimmunoprecipitated with HIF1A, but not TBP1, and did not promote degradation of HIF1A. Thus, the ability of pVHL to degrade HIF1A depends in part on its interaction with TBP1 and suggests a new mechanism for HIF1A stabilization in some pVHL-deficient tumors.
In a consanguineous Turkish pedigree with deafness, cataract, impaired intellectual development, and polyneuropathy (DCIDP; 619354), Kroll-Hermi et al. (2020) identified homozygosity for a deep intronic mutation in the PSMC3 gene (186852.0001) that segregated with disease and was not found in public variant databases.
By injection of morpholinos against psmc3, Kroll-Hermi et al. (2020) generated zebrafish morphants and observed that 95% of them showed cataract at 4 days postfertilization, compared to none of the controls. The morphants also displayed a smaller ear compared to controls and showed anomalies during semicircular canal morphogenesis, with canal projections failing to fuse in 79% of morphants compared to none of the controls. Similar results were obtained when CRISPER/Cas9 was used to knock down psmc3, and partial rescue of the lens and ear phenotype was effected with coinjection of gRNA2, Cas9, and psmc3 mRNA. Immunostaining of the inner ear hair bundle revealed a reduced number of cilia in 40% of crispants versus none of the controls. The morphology of the hair cells did not appear different in morphants compared to that of wildtype embryos, but the length of cilia was decreased in morphants.
In 2 male first cousins and their affected male third cousin from a consanguineous Turkish pedigree with deafness, cataract, impaired intellectual development, and polyneuropathy (DCIDP; 619354), Kroll-Hermi et al. (2020) identified homozygosity for an A-to-G transition in intron 10 (c.1127+337A-G) of the PSMC3 gene. The mutation segregated with disease and was not found in public variant databases, including gnomAD. RNA analysis in patient fibroblasts revealed that the variant causes inclusion of a cryptic 114-bp exon during splicing, predicted to result in addition of 15 amino acids followed by a stop codon (Ser376ArgfsTer15). There was a significantly reduced level of PSMC3 mRNA as well as the presence of an additional truncated form, but there was no difference in expression or localization of the PSMC3 protein between patient and control cells, indicating instability of the truncated form. There was an increased level of intracellular ubiquitinated proteins in patient cells compared to controls, suggesting that proteasomal proteolysis was less efficient. Control cells exposed to proteotoxic stress were able to compensate by upregulating their proteasome subunits, but patient cells could not. Rescue experiments revealed that the pool of ubiquitin-modified proteins was significantly reduced by about 20% in PSMC3-rescued patient fibroblasts at 24 hours posttransfection. In addition, the authors generated a zebrafish model with reduced psmc3 expression and observed lens opacities and inner ear anomalies.
Corn, P. G., McDonald, E. R., III, Herman, J. G., El-Deiry, W. S. Tat-binding protein-1, a component of the 26S proteasome, contributes to the E3 ubiquitin ligase function of the von Hippel-Lindau protein. Nature Genet. 35: 229-237, 2003. [PubMed: 14556007] [Full Text: https://doi.org/10.1038/ng1254]
DeMartino, G. N., Proske, R. J., Moomaw, C. R., Strong, A. A., Song, X., Hisamatsu, H., Tanaka, K., Slaughter, C. A. Identification, purification, and characterization of a PA700-dependent activator of the proteasome. J. Biol. Chem. 271: 3112-3118, 1996. [PubMed: 8621709] [Full Text: https://doi.org/10.1074/jbc.271.6.3112]
Hoyle, J., Tan, K. H., Fisher, E. M. C. Localization of genes encoding two human one-domain members of the AAA family: PSMC5 (the thyroid hormone receptor-interacting protein, TRIP1) and PSMC3 (the Tat-binding protein, TBP1). Hum. Genet. 99: 285-288, 1997. [PubMed: 9048938] [Full Text: https://doi.org/10.1007/s004390050356]
Kroll-Hermi, A., Ebstein, F., Stoetzel, C., Geoffroy, V., Schaefer, E., Scheidecker, S., Bar, S., Takamiya, M., Kawakami, K., Zieba, B. A., Studer, F., Pelletier, V., and 17 others. Proteasome subunit PSMC3 variants cause neurosensory syndrome combining deafness and cataract due to proteotoxic stress. EMBO Molec. Med. 12: e11861, 2020. [PubMed: 32500975] [Full Text: https://doi.org/10.15252/emmm.201911861]
Nelbock, P., Dillon, P. J., Perkins, A., Rosen, C. A. A cDNA for a protein that interacts with the human immunodeficiency virus Tat transactivator. Science 248: 1650-1653, 1990. [PubMed: 2194290] [Full Text: https://doi.org/10.1126/science.2194290]
Ohana, B., Moore, P. A., Ruben, S. M., Southgate, C. D., Green, M. R., Rosen, C. A. The type 1 human immunodeficiency virus Tat binding protein is a transcriptional activator belonging to an additional family of evolutionarily conserved genes. Proc. Nat. Acad. Sci. 90: 138-142, 1993. [PubMed: 8419915] [Full Text: https://doi.org/10.1073/pnas.90.1.138]
Sakao, Y., Kawai, T., Takeuchi, O., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Takeda, K., Akira, S. Mouse proteasomal ATPases Psmc3 and Psmc4: genomic organization and gene targeting. Genomics 67: 1-7, 2000. [PubMed: 10945464] [Full Text: https://doi.org/10.1006/geno.2000.6231]
Tanahashi, N., Suzuki, M., Fujiwara, T., Takahashi, E., Shimbara, N., Chung, C. H., Tanaka, K. Chromosomal localization and immunological analysis of a family of human 26S proteasomal ATPases. Biochem. Biophys. Res. Commun. 243: 229-232, 1998. [PubMed: 9473509] [Full Text: https://doi.org/10.1006/bbrc.1997.7892]