Background Lupus is a complex chronic systemic autoimmune disease. Dysregulation of interferon-alpha (IFN-) response has been associated with the pathogenesis of lupus. Genetic variants constitute the risk factors for the development of lupus, with many SNPs identified to pose the risk of lupus. However, the functions of the host genes of these SNPs are not fully understood. Recent studies show SNP rs4850410 is associated with serum IFN- levels in European-Americans and Afican-Americans. Rs4850410 is located in the intronic region of ANKRD44 which encodes a subunit of ankyin repeat domain of protein phosphatase 6 (PP6) that is involved in an array of important cellular processes, such as the regulation of metabolism, transcription, and apoptosis. However, if ANKRD44 regulates IFN responses is unknown. In this study, we aimed to investigate the function of ANKRD44 in controlling IFN response, and its association with the pathogenesis of lupus.
Methods PBMCs were collected from 46 SLE patients and 48 healthy controls. The mRNA expression of ANKRD44 and IFN-inducible genes was detected by real time PCR. The mRNA expression of ANKRD44 was measured at different time points in Raw264.7 cells during IFN stimulation. ANKRD44 was knocked down by using siRNA. The activation of IFN signaling pathway were examined by western blotting at different time points in Raw264.7 cells.
Results The mRNA expression levels of ANKRD44 were decreased in PBMCs from SLE patients compared to healthy controls. The expression of ANKRD44 was downregulated when stimulating by poly(I:C) or IFN in Raw264.7 cells. Knockdown of ANKRD44 up-regulated the expression of IFN-inducible genes (such as IFIT3 and CCL2). Consistently, knockdown of ANKRD44 promoted the phosphorylation of STAT1, STAT2, JAK1 and TYK2 stimulated by IFN in Raw264.7 cells.
Conclusions Our study indicates that ANKRD44 functions as a negative regulator in type I IFN signaling pathway. Decreased expression of ANKRD44 constitutes one of the mechanisms for dysregulated IFN response in SLE, which may play important roles in the pathogenesis of Lupus.
Funding Source(s): This work was supported by the National Basic Research Program of China (973 program) grant 2014CB541902 and the National Natural Science Foundation of China (No.81401331).
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