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

Abstract

Despite clinical use of immunosuppressive agents, the immunopathogenesis of minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) remains unclear. Src homology 3-binding protein 2 (SH3BP2), a scaffold protein, forms an immune signaling complex (signalosome) with 17 other proteins, including phospholipase Cγ2 (PLCγ2) and Rhoguanine nucleotide exchange factor VAV2 (VAV2). Bioinformatic analysis of human glomerular transcriptome (Nephrotic Syndrome Study Network cohort) revealed upregulated SH3BP2 in MCD and FSGS. The SH3BP2 signalosome score and downstream MyD88, TRIF, and NFATc1 were significantly upregulated in MCD and FSGS. Immune pathway activation scores for Toll-like receptors, cytokine-cytokine receptor, and NOD-like receptors were increased in FSGS. Lower SH3BP2 signalosome score was associated with MCD, higher estimated glomerular filtration rate, and remission. Further work using Sh3bp2 KI/KI transgenic mice with a gain-in-function mutation showed ~6-fold and ~25-fold increases in albuminuria at 4 and 12 weeks, respectively. Decreased serum albumin and unchanged serum creatinine were observed at 12 weeks. Sh3bp2 KI/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 importance of SH3BP2 in immune activation. SH3BP2 and its binding partners may determine the immune activation pathways resulting in podocyte injury leading to loss of the glomerular filtration barrier.

Understanding the podocyte immune responses in proteinuric kidney diseases: from pathogenesis to therapy

“…The Src homology 3 domain-binding protein 2 (SH3BP2) is an adaptor protein ubiquitously expressed in immune cells, governing signaling pathways within the cell ( 99 ). Kidney biopsy samples from patients with these conditions consistently exhibit upregulation of the SH3BP2 signaling complex, suggesting its potential involvement in immune activation—a prominent feature of these podocytopathies ( 100 ). Research led by Tarak Srivastava and colleagues, using murine models, has further underscored the significance of SH3BP2 in podocyte injury.…”

“…Research led by Tarak Srivastava and colleagues, using murine models, has further underscored the significance of SH3BP2 in podocyte injury. Transgenic mice with induced mutations in the SH3BP2 gene displayed features indicative of podocyte dysfunction, including elevated urinary albumin levels, a decrease in serum albumin, and an increase in mesangial cell proliferation ( 100 ). Collectively, these findings position SH3BP2 and its associated proteins at the forefront of immunological processes that contribute to podocyte injury.…”