PSMG2 is a chaperone protein that functions as a core component of proteasome assembly. It forms a heterodimer with PSMG1 and directly binds to proteasome subunits PSMA5 and PSMA7, promoting assembly of the alpha-ring structure of the 20S proteasome while preventing alpha-ring dimerization 1. This assembly function is critical for maintaining proteasomal protein degradation capacity and cellular protein homeostasis. Mutations in PSMG2 cause proteasome-associated autoinflammatory syndrome 4 (PRAAS), a type I interferonopathy. Loss-of-function PSMG2 mutations impair proteasome assembly, leading to accumulation of ubiquitinated proteins and triggering the unfolded protein response (UPR) and type I interferon signaling 23. Additionally, cytoplasmic mutant TDP-43 in neurological disorders interacts with PSMG2, impairing proteasomal activity and contributing to protein accumulation 4. Beyond autoinflammatory disease, PSMG2 has emerging roles in cancer biology. High PSMG2 expression correlates with poor prognosis in head and neck squamous cell carcinoma and triple-negative breast cancer 15. PSMG2 downregulation reduces tumor proliferation, stemness, and chemotherapy resistance by causing protein accumulation, ER stress, and activating compensatory autophagy and apoptosis pathways 15. PSMG2 expression is transcriptionally regulated by NFE2L1/NFE2L3 to maintain basal proteasome activity 6.