The m⁶A demethylase FTO links TLR7 to mitochondrial oxidation driving age-associated B cell formation in systemic lupus erythematosus.

Abstract

Extrafollicular age-associated B cells (ABCs) excessively expand and produce autoantibodies in systemic lupus erythematosus (SLE), and the regulatory mechanism remains elusive. We found that the m⁶A demethylase fat mass and obesity-associated protein (FTO) was highly expressed in ABCs from patients with SLE, which was positively associated with renal immune damage. FTO overexpression in murine and human B cells facilitated ABC expansion and exacerbated SLE in lupus-prone mice, whereas FTO ablation ameliorated ABC-driven autoimmunity. FTO expression was up-regulated upon activation of the toll-like receptor 7-myeloid differentiation primary response protein 88 (TLR7-MyD88) signaling pathway. FTO, in turn, promoted TLR7-driven ABC differentiation by targeting ATPase H⁺ transporting V1 subunit G1 (ATP6V1G1), a subunit of the vacuolar H⁺-ATPase (V-ATPase), in an m⁶A-dependent manner. Mechanistically, FTO deficiency impaired lysosomal autophagy by reducing ATP6V1G1-mediated V-ATPase activity. The accumulation of damaged mitochondria led to mitochondrial dysfunction in human and murine B cells, characterized by reduced oxidative phosphorylation and elevated reactive oxygen species. This dysfunction limited cell proliferation and blocked ABC differentiation by dampening cellular responsiveness to interleukin-12. Thus, TLR7-FTO-ATP6V1G1 signaling metabolically shapes extrafollicular ABCs in SLE, providing a potential therapeutic target.