Regulation of ZAP-70 post-translational modifications by HIV-1 accessory proteins Nef and Vpu
Abstract
Human Immunodeficiency virus type 1 (HIV-1) downregulates major histocompatibility complex I (MHC-I) from the surface of infected cells to evade the immune response by cytotoxic T lymphocytes. To accomplish this, the HIV-1 protein Nef first interacts with Src family kinases (SFKs) to phosphorylate zeta-associated protein 70 producing regulatory post-translational modifications (PTMs). This research investigated the effects of HIV-1 on ZAP-70 regulation, which ZAP-70 PTMs are critical for MHC-I downregulation, and explored the effects of Nef:SFK inhibitors on ZAP-70 PTMs. I found that HIV-1 increases the total level of ZAP-70 along with ZAP-70 pTyr292 and pTyr319 PTMs. Furthermore, these effects are primarily Nef-dependent and are modulated by the related HIV-1 protein Vpu. Pharmacological inhibitors were validated as capable of disrupting the Nef:SFK interaction and variably affected ZAP-70 signalling and MHC-I restoration. Together these findings highlight the multifaceted regulation of ZAP-70 by specific defined HIV-1 proteins.