Alt. symbols: MECL1 | LMP10 | MGC1665 | beta2i

Approved name: proteasome 20S subunit beta 10
Alt. names: proteasome (prosome, macropain) subunit, beta type, 10, proteasome subunit beta 10 | proteasome subunit ?2i

Location: 16q22.1: 67934506 - 67936864 (-)
Gene type: protein_coding, 5 transcripts.

Scores: LoFtool: 0.693000 | pLI: 0.00002340 | LOEUF: 1.366

HGNC: 9538

NCBI: 5699, RefSeq: .0

Ensembl: ENSG00000205220.12

LRG_ | Status: none

OMIM: 176847

Expression | ProteinAtlas

Proteasomes are multiprotein complexes with ATP-dependent proteolytic activities essential for intracellular clearance of K48 ubiquitin-tagged peptides and antigen processing to generate class I binding peptides. Proteasome maturation protein (POMP) serves as a chaperone for proteasome assembly and is degraded by the same proteasome upon completion of maturation. Immune cells contain a specialized immunoproteasome (i20S) that selectively incorporates specialized β1i (PSMB9/LMP2), β2i (PSMB10/LMP-10/MECL-1), and β5i (PSMB8/LMP7) catalytic subunits. During an immunological challenge, non-immune cells are stimulated by immune response products (IFN-γ or TNF-alpha), to upregulate i20S and enhance antigen presentation via class I major histocompatibility complex (MHC-I) molecules, allowing for the generation of an appropriate specific T cell response with subsequent T cell expansion and survival.

Autosomal-recessive (AR) or digenic LOF mutations in constitutive 20S proteasome subunits or immunoproteasome-specific catalytic subunits cause Proteasome-associated autoinflammatory syndromes (PRAAS) [OMIM: 256040]. (See PRAAS5 entry for clinical details). These mutations impair proteasomal assembly, maturation and/or activity, leading to intracellular accumulation of undegraded proteins, ER stress, the unfolded protein response (UPR) and inappropriate type I IFN activation. There has thus far only been one report of a PRAAS patient with homozygous mutations in PSMB10 [OMIM: 619175, PRAAS5]. Van der Made et al. (2024) recently reported the identification of 3 de novo heterozygous missense PSMB10 variants in 6 unrelated infants with T-B-NK± SCID and Omenn-like presentations (PMID: 38503300). (See SCID18 entry for details). All infants received alloHSCT but exhibited a variety of severe inflammatory complications thereafter, with 2 peri-transplant and 2 delayed deaths. The lone survivor showed evidence of genetic rescue through revertant mosaicism overlapping the affected PSMB10 locus. The identified variants were predicted in silicoto profoundly disrupt 20S immunoproteasome structure through impaired β-ring/β-ring interaction. Recently, Ghosh et al. from Dussedorf identified another de novo heterozygous PSMB10 variant (G209R) in a newborn with severe T cell lymphopenia. They showed that PSMB10-deficient primary HSCs were able to differentiate via co-culture with 3D ATOs into T cells. Clinically, the patient became T cell proficient within the first year of life developing normal naïve T cell counts with a normal TCR repertoire. Thus, the authors concluded that the mechanistic defect resided in TECs and not in the lymphocytes, potentially explaining why the prior patients had failed HSCT and suggesting the use of thymic transplantation in refractory cases. [Publication pending, presented at ESID 2024] [Load More]