Silencing ZAP70 prevents HSP65-induced reverse cholesterol transport and NF-κB activation in T cells.

T cell activation by antigens binding to the T cell receptor (TCR) must be properly regulated to ensure normal T cell development. The ζ chain-associated 70-kDa protein (ZAP70) is sequentially activated in response to TCR engagement and serves as a critical component of the TCR signaling pathway, which is essential for T cell activation. However, some roles of ZAP70 have not been fully elucidated. In the present study, we analyzed the effects of ZAP70 on the cholesterol efflux rate, nuclear factor κB (NF-κB) activation and cell proliferation in T cells. Our study showed that silencing ZAP70 increased the cholesterol efflux rate in T cells. We also found that silencing ZAP enhanced the expression of ATP-binding cassette transporter A1 (ABCA1), ATP-binding cassette transporter G1 (ABCG1), scavenger receptor-BI (SR-BI) peroxisome proliferator-activated receptor-gamma (PPAR-γ) and liver X receptor-alpha (LXR-α). In contrast, the phosphorylation of ZAP70 by HSP65 decreased the cholesterol efflux rate and the expression of five cholesterol transport proteins in T cells. The phosphorylation of ZAP70 activated the downstream NF-κB signaling pathway, which is involved in both T cell growth and function. Furthermore, silencing ZAP70 inhibited T cell proliferation. These results indicate a crucial and unexpected role for ZAP70 in the physiological activities of T cells, suggesting that inhibition of ZAP70 is beneficial for anti-atherosclerosis.