CASTOR1 Regulates Humoral Immune Responses and Contributes to the Pathogenesis of Systemic Lupus Erythematosus

OBJECTIVE: CASTOR1 senses arginine and regulates mammalian target of rapamycin complex 1 (mTORC1), a central metabolic signaling molecule. This study aimed to elucidate the roles of CASTOR1 in humoral immune responses. METHODS: We analyzed human B cell transcriptomes from healthy controls and patients with systemic lupus erythematosus (SLE) via correlation analysis and gene set variation analysis using our database, Immune Cell Gene Expression Atlas from the University of Tokyo. Castor1-deficient and B cell-specific Castor1-deficient mice were used for analyses of serum immunoglobulins and autoantibodies, urinary proteins, renal pathology, gene expression, and flow cytometry in spleen and bone marrow cells. The culture supernatant of splenic B cells was used for immunoglobulin (Ig) analysis. RESULTS: Transcriptomic analysis of bulk RNA sequencing data from various B cell subsets in patients with SLE (n = 136; n = 129 included in the primary analysis) revealed a correlation between CASTOR1 expression and disease activity, with CASTOR1 expression in plasmablasts inversely correlated with Systemic Lupus Erythematosus Disease Activity Index 2000 (r = -0.32, P = 0.00031). Castor1-deficient mice exhibited increased plasma cell populations in the spleen and bone marrow, elevated serum IgG levels, production of anti-double-stranded DNA antibodies, and glomerulonephritis with IgG deposits, reflecting SLE-like autoimmunity. Moreover, B cell-specific Castor1-deficient mice showed increased plasma cell counts, elevated serum IgG levels, and glomerulonephritis, indicating that Castor1 might regulate systemic humoral immunity via a B cell-intrinsic mechanism. CONCLUSION: CASTOR1 plays a regulatory role in humoral immunity and may contribute to the pathogenesis of autoimmune diseases such as SLE, representing a potential therapeutic target.