Scaffold protein SH3BP2 signalosome is pivotal for immune activation in nephrotic syndrome.

Despite clinical use of immunosuppressive agents, the immunopathogenesis of Minimal Change Disease (MCD) and Focal Segmental Glomerulosclerosis (FSGS) remains unclear. SH3BP2, a scaffold protein, forms an immune signaling complex (signalosome) with seventeen other proteins including PLCγ2 and VAV2. Bioinformatic analysis of human glomerular transcriptome (NEPTUNE cohort) revealed upregulated SH3BP2 in MCD (p=0.001) and FSGS (p<0.001). The SH3BP2-signalosome score and downstream MYD88, TRIF, and NFATc1 were significantly upregulated in MCD and FSGS (p=0.004-0.001). Immune pathway activation scores for Toll-like receptors (p=0.042), Cytokine-Cytokine receptor (p=0.001) and NOD-like receptors (p=0.042) were increased in FSGS. Lower SH3BP2-signalosome score was associated with MCD, higher eGFR and remission. Further work using Sh3bp2KI/KI transgenic mice with a gain-in-function mutation showed ~6 and ~25-fold increase in albuminuria at 4 and 12 weeks, respectively. Decreased serum albumin (p=0.002) and unchanged serum creatinine were observed at 12 weeks. Sh3bp2KI/KI kidney morphology appeared normal except for increased mesangial cellularity and patchy foot process fusion without electron dense deposits. SH3BP2 co-immunoprecipitated with PLCγ2 and VAV2 in human podocytes underscoring the significance of SH3BP2 in immune activation. SH3BP2 and its binding partners likely determine the immune activation pathways resulting in podocyte injury leading to loss of glomerular filtration barrier.