Alt. symbols: TNFSF5IP1 | HCCA3 | MDS003 | MGC15092 | CLAST3 | HsT1707 | PAC2

Approved name: proteasome assembly chaperone 2
Alt. names: tumor necrosis factor superfamily, member 5-induced protein 1, proteasome (prosome, macropain) assembly chaperone 2 | hepatocellular carcinoma susceptibility protein, CD40 ligand-activated specific transcript 3

Location: 18p11.21: 12658043 - 12728945 (+)
Gene type: protein_coding, 23 transcripts.

Scores: LoFtool: 0.300000 | pLI: 0.00355676 | LOEUF: 1.443

HGNC: 24929

NCBI: 56984, RefSeq: .0

Ensembl: ENSG00000128789.22

LRG_ | Status: none

OMIM: 609702

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. PSMG2 encodes a chaperone protein that helps promote assembly of the 20S proteasome as part of a heterodimer with PSMG1 (PMID: 30664889). This heterodimer binds to the PSMA5 and PSMA7 proteasome subunits to promote assembly of the proteasome alpha subunits into the heteroheptameric alpha ring and prevent alpha ring dimerization.

Recently, compound heterozygous PSMG2 mutations were identified in a patient with features of PRAAS and autoimmune hemolytic anemia [OMIM: 619183, PRAAS4] (PMID: 30664889). 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 e vidence of neutrophilic dermatosis on biopsy), and lipodystrophy, in addition to intra- and/or extra-cranial calcinosis, myositis, lymphadenopathy, hepatosplenomegaly, progressive 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). [Load More]