The switch from proteasome to immunoproteasome is increased in circulating cells of patients with fast progressive immunoglobulin A nephropathy and associated with defective CD46 expression

Abstract

The proteasome to immunoproteasome (iPS) switch consists of β1, β2 and β5 subunit replacement by low molecular weight protein 2 (LMP2), LMP7 and multicatalytic endopeptidase-like complex-1 (MECL1) subunits, resulting in a more efficient peptide preparation for major histocompatibility complex 1 (MHC-I) presentation. It is activated by toll-like receptor (TLR) agonists and interferons and may also be influenced by genetic variation. In a previous study we found an iPS upregulation in peripheral cells of patients with immunoglobulin A nephropathy (IgAN). We aimed to investigate in 157 IgAN patients enrolled through the multinational Validation Study of the Oxford Classification of IgAN (VALIGA) study the relationships between iPS switch and estimated glomerular filtration rate (eGFR) modifications from renal biopsy to sampling. Patients had a previous long follow-up (6.4 years in median) that allowed an accurate calculation of their slope of renal function decline. We also evaluated the effects of the PSMB8/PSMB9 locus (rs9357155) associated with IgAN in genome-wide association studies and the expression of messenger RNAs (mRNAs) encoding for TLRs and CD46, a C3 convertase inhibitor, acting also on T-regulatory cell promotion, found to have reduced expression in progressive IgAN. We detected an upregulation of LMP7/β5 and LMP2/β1 switches. We observed no genetic effect of rs9357155. TLR4 and TLR2 mRNAs were found to be significantly associated with iPS switches, particularly TLR4 and LMP7/β5 (P < 0.0001). The LMP7/β5 switch was significantly associated with the rate of eGFR loss (P = 0.026), but not with eGFR at biopsy. Fast progressors (defined as the loss of eGFR >75th centile, i.e. −1.91 mL/min/1.73 m2/year) were characterized by significantly elevated LMP7/β5 mRNA (P = 0.04) and low CD46 mRNA expression (P < 0.01). A multivariate logistic regression model, categorizing patients by different levels of kidney disease progression, showed a high prediction value for the combination of high LMP7/β5 and low CD46 expression.

Weighted Gene Co-expression Network Analysis Reveals Different Immunity but Shared Renal Pathology Between IgA Nephropathy and Lupus Nephritis

“…In addition, PSMB8 and PSMB9, the hub genes in blue module, have been identified as the susceptibility genes for IgAN by GWAS (Kiryluk et al, 2012), although our GWAS enrichment analysis suggested blue module was not enriched in IgAN, which might be limited by the samples size of IgAN data. More importantly, PSMB8 and PSMB9 were found to be involved in the transformation of peripheral blood proteasome to immunoproteasome, which is closely related to the exacerbation of IgAN (Peruzzi et al, 2020). Furthermore, PSMB8 and PSMB9 have been identified as the core genes related to immune cells in kidney and a "cross-talk" gene of glomerulus and tubules by two other LN expression profile studies (Cao et al, 2019;Yao et al, 2020).…”

Blood Immunoproteasome Activity Is Regulated by Sex, Age and in Chronic Inflammatory Diseases: A First Population-Based Study

“…Immunoproteasome function is dysregulated in multiple chronic diseases. Activation of the immunoproteasome has been reported as a pathomechanistic feature of autoimmune disorders with elevated expression of immunoproteasome subunits in circulating lymphocytes of patients with Sjögren’s Syndrome, myositis, and nephropathies [ 21 , 22 , 23 , 24 ]. Similarly, we recently observed that immunoproteasome activity is activated in peripheral blood mononuclear cells (PBMCs) of patients with severe chronic obstructive pulmonary diseases (COPD), a major tobacco smoke related lung disease [ 25 ].…”

Exploring the crosstalk molecular mechanisms between IgA nephropathy and Sjögren’s syndrome based on comprehensive bioinformatics and immunohistochemical analyses

“…The PSMB8 and PSMB9 genes code for low molecular weight protein 7 (LMP7) and LMP2, respectively, involved in the proteasome switch and antigen processing to generate major histocompatibility complex class I binding peptides, and then contribute to the activation of lymphocyte in the IgAN [17]. In a genomewide association research, rs9357155 at the PSMB8/9 locus was related to an increased risk of IgAN[18].…”