Nucleosomal double-stranded DNA triggers APOL1 expression through the STINGTBK1-IRF3 pathway

Abstract

Abstract African Americans are four times more likely to develop kidney disease. Racial disparities in the frequency of nondiabetic kidney disease has led to the discovery of the apolipoprotein L1 (APOL1) gene variants, G1 and G2, which exist exclusively in individuals of recent African ancestry. The presence of these kidney risk alleles strongly correlates with several forms of nondiabetic kidney disease including lupus nephritis (LN). However, the mechanism by which APOL1 variants lead to a faster progression to LN in systemic lupus erythematosus (SLE) patients carrying APOL1 risk alleles is unclear. Increased levels of type I interferons (IFNs) and nucleosomal dsDNA fragments (nsDNA) in the blood is the hallmark of lupus erythematosus. We hypothesize that accumulation of dsDNA in the cytosol of podocytes that play a key role in maintenance of the filtration barrier in the kidney activates the DNA sensing pathways leading to expression of type I IFNs and proinflammatory cytokines damaging podocytes. Although type I IFNs stimulate APOL1 expression, it is unknown whether dsDNA induces APOL1 accumulation independently of IFN. Here we show that nsDNA triggers the expression of APOL1 through the activation of the cGAS/IFI16-STING-TBK1-IRF3 pathway. We have also shown that inhibition of type I IFN only partly inhibited APOL1 accumulation in podocytes, demonstrating that nsDNA directly activates expression of the APOL1 gene. We conclude that blocking type I IFN signaling and targeting elements of the nsDNA-induced pathway may represent a novel therapeutic approach to inhibit LN progression in African Americans SLE patients carrying APOL1 kidney risk alleles.