Alternative titles; symbols
HGNC Approved Gene Symbol: PSMB5
Cytogenetic location: 14q11.2 Genomic coordinates (GRCh38): 14:23,025,851-23,035,220 (from NCBI)
Proteasomes are the proteolytic complex responsible for major histocompatibility complex (MHC) class I-restricted antigen presentation (Akiyama et al., 1994).
See PSMB2 (602175) for further discussion of beta-type proteasome subunits.
Akiyama et al. (1994) cloned the full-length cDNA and showed that PSMB5 has high amino acid similarity to PSMB8 (177046).
Akiyama et al. (1994) showed that treatment with interferon-gamma (IFNG; 147570) increased expression of MHC-encoded LMP2 (PSMB9; 177045) and LMP7 (PSMB8; 177046) subunits of the proteasome and decreased expression of 2 proteasomal subunits PSMB5 and PSMB6, which altered the proteolytic specificity of proteasomes. IFNG may induce subunit replacements of PSMB5 and PSMB6, producing proteasomes that may be more appropriate for the immunologic processing of endogenous antigens.
Bortezomib, a reversible proteasome inhibitor used in the treatment of refractory multiple myeloma (see 254500), targets primarily the chymotrypsin-like activity of PSMB5. To study the molecular basis of bortezomib resistance, Oerlemans et al. (2008) generated high levels of acquired resistance in human myelomonocytic THP1 cells by exposure to stepwise increasing concentrations of bortezomib. Analysis of resistant cells revealed that those with higher levels of resistance were homozygous for a missense mutation in the highly conserved substrate/inhibitory binding domain of PSMB5. In addition, there was dramatic overexpression of PSM5B protein, but not of other proteasome subunits. RNAi-mediated silencing of PSMB5 expression resulted in restoration of bortezomib sensitivity in resistant cells. Oerlemans et al. (2008) concluded that bortezomib resistance is associated with selective overexpression of a mutant PSMB5 protein.
The PSMB5 gene was mapped to chromosome 14q11.2 by Belich et al. (1994). McCusker et al. (1997) demonstrated that the PSMB5 gene is located on 14q11.2 within 1 Mb of the genes encoding the alpha (600654) and beta (602161) subunits of the PA28 complex.
Akiyama, K., Yokota, K., Kagawa, S., Shimbara, N., Tamura, T., Akioka, H., Nothwang, H. G., Noda, C., Tanaka, K., Ichihara, A. cDNA cloning and interferon gamma down-regulation of proteasomal subunits X and Y. Science 265: 1231-1234, 1994. [PubMed: 8066462] [Full Text: https://doi.org/10.1126/science.8066462]
Belich, M. P., Glynne, R. J., Senger, G., Sheer, D., Trowsdale, J. Proteasome components with reciprocal expression to that of the MHC-encoded LMP proteins. Curr. Biol. 4: 769-776, 1994. [PubMed: 7820546] [Full Text: https://doi.org/10.1016/s0960-9822(00)00174-3]
McCusker, D., Jones, T., Sheer, D., Trowsdale, J. Genetic relationships of the genes encoding the human proteasome beta subunits and the proteasome PA28 complex. Genomics 45: 362-367, 1997. [PubMed: 9344661] [Full Text: https://doi.org/10.1006/geno.1997.4948]
Oerlemans, R., Franke, N. E., Assaraf, Y. G., Cloos, J., van Zantwijk, I., Berkers, C. R., Scheffer, G. L., Debipersad, K., Vojtekova, K., Lemos, C., van der Heijden, J. W., Ylstra, B., Peters, G. J., Kaspers, G. L., Dijkmans, B. A. C., Scheper, R. J., Jansen, G. Molecular basis of bortezomib resistance: proteasome subunit beta-5 (PSMB5) gene mutation and overexpression of PSMB5 protein. Blood 112: 2489-2499, 2008. [PubMed: 18565852] [Full Text: https://doi.org/10.1182/blood-2007-08-104950]