Proteasome is a large protein complex, which degrades most intracellular proteins. It regulates numerous cellular processes, including the removal of misfolded or unfolded proteins, cell cycle control, and regulation of apoptosis. However, the function of proteasome subunits in viral immunity has not been well characterized. In this study, we identified PSMB1, a member of the proteasome β subunits (PSMB) family, as a negative regulator of innate immune responses during viral infection. Knockdown of PSMB1 enhanced the RNA virus-induced cytokine and chemokine production. Overexpression of PSMB1 abolished virus-induced activation of the interferon-stimulated response element (ISRE) and interferon beta (IFNβ) promoters. Mechanistically, PSMB1 inhibited the activation of RIG-I-like receptor (RLR) and Toll-like receptor 3 (TLR3) signaling pathways. PSMB1 was induced after viral infection and its interaction with IKK-ε promoted degradation of IKK-ε through the ubiquitin-proteasome system. Collectively, our study demonstrates PSMB1 is an important regulator of innate immune signaling.

To explore whether the variants in non MHC proteasome gene are associated with AS and explain the role of the variant in the disease. Case-control analysis to identify AS predisposition genes; dual-luciferase reporter assay, immunoblot analysis and osteoclastogenesis assays to detect the function of the positive variant. Affected individuals were diagnosed according to the modified New York Criteria by at least two experienced rheumatologists, and rechecked by another rheumatologist. The study included 1037 AS patients and 1014 no rheumatic and arthritis disease controls. The main age of AS onset is between 16 and 35 years old. HLA-B27-positive subjects comprised 90.0% of patients. A nonsynonymous SNP rs12717 in proteasome gene PSMB1 significantly associated with AS. Individuals with CC genotype had a higher onset risk compared with those with GG/GC genotypes (OR = 1.89, P = 0.0047). We also discovered that PSMB1 regulates the receptor activator of nuclear factor-κB (RANK)/RANK ligand (RANKL) signalling pathway and the disease-associated variant PSMB1-Pro11 significantly inhibits RANKL-induced NF-κB pathway in osteoclast differentiation via the degradation of IKK-β compared with PSMB1-Ala11. RANKL induced osteoclast differentiation was significantly lower in primary monocyte osteoclast precursor from individuals with genotype PSMB1^31C/31C compared with individuals with genotype PSMB1^31G/31G. These results reveal a novel understanding of the bone formation and reabsorbing imbalance in AS. The new bone formation phenotype can be attributed to the inhibition of osteoclast differentiation by a more functional PSMB1 gene.

Introduction: Porokeratosis (PK) is an autoinflammatory keratinization disease (AIKD) characterized by circular or annular skin lesions with a hyperkeratotic rim, pathologically shown as the cornoid lamella. Four genes that cause PK are associated with the mevalonate (MV) pathway. In Chinese PK patients, mevalonate diphosphate decarboxylase ( MVD ) is the most common causative gene. The lack of an animal model has greatly limited research on PK pathogenesis. Materials and Methods: In this research, we constructed K14‐CreER ^T2 ‐ Mvd ^fl/fl mice using the Cre‐LoxP system to create a mouse model for in‐depth studies of PK. The Epidermal Mvd gene was knocked out by intraperitoneal injection of Tamoxifen (TAM). Pathology, immunohistochemistry, RNA‐seq, and Western Blot analysis were performed. Results: Skin lesions appeared following Mvd deficiency, and pathological examination revealed the characteristic cornoid lamella, as well as cutaneous inflammation. Furthermore, we observed elevated levels of IL‐17A and IL‐1β, and a decreased Loricrin level in epidermal Mvd‐deficient mice. Compared with the wild‐type (WT) group, Mvd deficiency activated the expression of lipid metabolism‐related proteins. Conclusion: We developed the first mouse model for PK research, enabling further studies on disease development and treatment approaches.