Geranylgeranylation is required for B-cell proliferation and plasma cell survival implications for autoimmune therapy

Tissue-resident long-lived plasma cells, whose current therapies fail to effectively eliminate them, are now recognized as key factors in refractory and relapsed autoimmune diseases such as systemic lupus erythematosus (SLE). In this study, we discovered that the most commonly used cholesterol-lowering drugs in clinical practice, particularly lipophilic statins, can deplete antibody-secreting cells (ASCs) by triggering endoplasmic reticulum stress (ERS)-mediated apoptosis. Supplementation with geranylgeranyl pyrophosphate (GGPP) completely counteracted the effects of statins on ASCs. Targeting geranylgeranyltransferase type II (GGTase Ⅱ) downstream of GGPP through the use of 3-PEHPC, a chemical inhibitor of GGTase Ⅱ, replicated the destructive effects of statins on ASCs. Additionally, by generating mice with B-cell-specific deletion of Rabggta, which encodes RABGGTA, the specific subunit of GGTase II, we further demonstrated that GGTase II is critical for antibody responses, as well as for the generation of germinal centers, memory B cells, and bone marrow plasma cells. Mechanistically, GGTase II is essential for B-cell activation and proliferation and for protecting B cells from cell death triggered by mitogenic signals. Furthermore, GGTase Ⅱ deficiency in B cells impeded disease progression in lupus-like mice. Both 3-PEHPC and atorvastatin were effective at alleviating disease activity in these lupus-like models, resulting in significant depletion of ASCs. In conclusion, our study highlights GGTase II as a potential therapeutic target for autoimmune diseases and highlights the promising role of statins in their treatment.