Nakajo-Nishimura syndrome At least one mutation in the PSMB8 gene has been found to cause Nakajo-Nishimura syndrome, a condition that has been described only in the Japanese population. The identified mutation changes a single protein building block (amino acid) in the protein produced from the PSMB8 gene, replacing the amino acid glycine with the amino acid valine at protein position 201 (written as Gly201Val or G201V). This mutation greatly reduces the production of this protein, which impairs the normal assembly of immunoproteasomes and causes the immune system to malfunction. For unknown reasons, the malfunctioning immune system triggers abnormal inflammation that can damage tissues throughout the body. Abnormal inflammation likely underlies many of the signs and symptoms of Nakajo-Nishimura syndrome, including the development of red, swollen lumps (nodular erythema) on the skin, recurrent fevers, joint problems, and an enlarged liver and spleen (hepatosplenomegaly). It is less clear how mutations in the PSMB8 gene lead to other characteristic features of the condition, including muscle weakness and wasting and a loss of fatty tissue (lipodystrophy), mainly in the upper body. Because the protein produced from the PSMB8 gene may be involved in the maturation of adipocytes, studies suggest that a shortage of this protein may interfere with the normal development and function of these cells. other disorders Mutations in the PSMB8 gene have also been found in two conditions with signs and symptoms that overlap with those of Nakajo-Nishimura syndrome: one called joint contractures, muscular atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP) syndrome; and the other called chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome. All three conditions are characterized by skin abnormalities and lipodystrophy. Although they are often considered separate disorders, some researchers believe they may represent different forms of a single condition. One PSMB8 gene mutation has been identified in families with JMP syndrome and in families with CANDLE syndrome. This mutation replaces the amino acid threonine with the amino acid methionine at protein position 75 (written as Thr75Met or T75M). Another mutation has been found only in people with CANDLE syndrome; it replaces the amino acid cysteine with a signal to stop protein production prematurely (written as Cys135Ter or C135X). Each of these mutations greatly reduces protein production from the PSMB8 gene. It is unclear how mutations in this gene lead to the overlapping but distinct patterns of signs and symptoms in Nakajo-Nishimura syndrome, JMP syndrome, and CANDLE syndrome. Researchers speculate that mutations in different areas of the gene may have different effects on protein function.

     The PSMB8 gene provides instructions for making one part (subunit) of cell structures called immunoproteasomes. Immunoproteasomes are specialized versions of proteasomes, which are large complexes that recognize and break down (degrade) unneeded, excess, or abnormal proteins within cells. This activity is necessary for many essential cell functions. While proteasomes are found in many types of cells, immunoproteasomes are located primarily in immune system cells. These structures play an important role in regulating the immune system's response to foreign invaders, such as viruses and bacteria. One of the primary functions of immunoproteasomes is to help the immune system distinguish the body's own proteins from proteins made by foreign invaders, so the immune system can respond appropriately to infection. Immunoproteasomes may also have other functions in immune system cells and possibly in other types of cells. They appear to be involved in some of the same fundamental cell activities as regular proteasomes, such as regulating the amount of various proteins in cells (protein homeostasis), cell growth and division, the process by which cells mature to carry out specific functions (differentiation), chemical signaling within cells, and the activity of genes. Studies suggest that, through unknown mechanisms, the subunit produced from the PSMB8 gene in particular may be involved in the maturation of fat cells (adipocytes).

The following transcription factors affect gene expression:

• NF-kappaB
• Egr-1
• AP-1
• NF-kappaB1
• STAT1
• STAT1beta
• STAT1alpha
• SREBP-1a
• SREBP-1c
• SREBP-1b

Induction:

Up-regulated by IFNG/IFN-gamma and IRF1 (at protein level). Up-regulated by TNF (at protein level). Up-regulated by tetrodotoxin (TTX) in glial cells. Up-regulated in Crohn's bowel disease (CD). Down-regulated by the selective inhibitor PR-957. Down-regulated in mature dendritic cells by HSV-1 infection. Up-regulated by heat shock treatment.

Developmental stage:

Highly expressed in immature dendritic cells (at protein level).

Molecular Function:

• Threonine-Type Endopeptidase Activity

Biological Processes:

• Anaphase-Promoting Complex-Dependent Catabolic Process
• Antigen Processing And Presentation Of Exogenous Peptide Antigen Via Mhc Class I, Tap-Dependent
• Fat Cell Differentiation
• Fc-Epsilon Receptor Signaling Pathway
• Mapk Cascade
• Negative Regulation Of Canonical Wnt Signaling Pathway
• Negative Regulation Of Ubiquitin-Protein Ligase Activity Involved In Mitotic Cell Cycle
• Nik/Nf-Kappab Signaling
• Positive Regulation Of Canonical Wnt Signaling Pathway
• Positive Regulation Of Ubiquitin-Protein Ligase Activity Involved In Regulation Of Mitotic Cell Cycle Transition
• Proteasome-Mediated Ubiquitin-Dependent Protein Catabolic Process
• Protein Polyubiquitination
• Regulation Of Cellular Amino Acid Metabolic Process
• Regulation Of Endopeptidase Activity
• Regulation Of Mrna Stability
• Stimulatory C-Type Lectin Receptor Signaling Pathway
• T Cell Receptor Signaling Pathway
• Tumor Necrosis Factor-Mediated Signaling Pathway
• Type I Interferon Signaling Pathway
• Viral Process
• Wnt Signaling Pathway, Planar Cell Polarity Pathway

Drug Bank:

• Carfilzomib