Proteasome subunit beta type-4

PSMB4 encodes proteasome subunit beta type-4, a non-catalytic component of the 20S core proteasome complex (UniProt: P28070). This subunit participates in proteolytic degradation of intracellular proteins, functioning within the 26S proteasome to mediate ATP-dependent degradation of ubiquitinated substrates and maintain protein homeostasis by removing misfolded or damaged proteins. The protein also mediates ubiquitin-independent proteolysis when associated with regulatory particles PA200 or PA28.

PSMB4 is expressed broadly across tissues as part of the essential proteasomal degradation machinery (UniProt: P28070). Beyond its housekeeping role, pathogenic variants in PSMB4 are associated with proteasome-associated autoinflammatory syndrome 3 (PRAAS3), an autosomal recessive disorder characterized by early-onset fever, dermatitis, myositis, and immune dysregulation.

In Alzheimer's disease, PSMB4 shows downregulation in post-mortem AD brain tissue compared to age-matched controls (mean log2FC: −0.35, Chaparral AD proteomics). This reduced proteasomal capacity may impair clearance of misfolded proteins, including amyloid-beta and tau aggregates, potentially contributing to proteostatic dysfunction in AD pathogenesis.