Alt. symbols: LMP2 | RING12 | beta1i | PSMB6i

Approved name: proteasome 20S subunit beta 9
Alt. names: proteasome (prosome, macropain) subunit, beta type, 9 (large multifunctional protease 2), large multifunctional peptidase 2, proteasome (prosome, macropain) subunit, beta type, 9, proteasome subunit beta 9 | proteasome subunit ?1i

Location: 6p21.32: 32844136 - 32860734 (+)
Gene type: protein_coding, 5 transcripts.

Scores: LoFtool: 0.733000 | pLI: 0.22564703 | LOEUF: 0.955

HGNC: 9546

NCBI: 5698, RefSeq: .0

Ensembl: ENSG00000240065.9

LRG_ | Status: none

OMIM: 177045

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-α), 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) biallelic or digenic LOF mutations in constitutive 20S proteasome subunits or immunoproteasome-specific catalytic subunits cause Proteasome-associated autoinflammatory syndromes (PRAAS), characterized by early-onset recurrent fevers, periorbital erythema and swelling, skin lesions (panniculitis with evidence of neutrophilic dermatosis on biopsy), and lipodystrophy, in addition to intra- and/or extra-cranial calcinosis, myositis, lymphadenopathy, hepatosplenomegaly, progr essive joint contractures, metabolic syndrome, recurrent infections and multi-organ failure [OMIM: 256040]. 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. Patients may be triggered by acute stressors such as cold, physical stress, or infections, leading to a vicious feed-forward cycle of inflammatory chemokine and cytokine production by both hematopoietic and nonhematopoietic cells that may affect any organ. Immunophenotyping may be unremarkable or show overt lymphocyte subset abnormalities and patients can have nonspecifically elevated inflammatory markers, cytopenias, transaminitis, dyslipidemia, hypergammaglobulinemia and variable autoantibody production, along with increased type I IFN production and strong peripheral blood ISGs. JAK inhibitors have been shown to ameliorate disease activity (PMID: 29649002), while HSCT can be curative (PMID: 34416217, 34131834, 33727065). Recently, a heterozygous de novo PSMB9 mutation (G156D) was reported to cause AD PRAAS in 2 unrelated patients (PMID: 34819510, 33727065). This mutation was found to dominant negatively suppress protease activity. One of the patients was successfully treated with JAK inhibition and then HSCT. Additionally, a subset of patients with severe phenotypes have been reported to carry digenic mutations at two separate proteasomal loci (PSMB8 and PSMA3, PSMB8 and PSMB4, or PSMB9 and PSMB4) [OMIM: 617591, PRAAS3] (PMID: 26524591). [Load More]