Low-density lipoprotein receptor-related protein 1 mediates α1-antitrypsin internalization in CD4+ T lymphocytes. Issue 6 (23rd July 2015)

• Record Type: Journal Article
• Authors: Zhou, Xueyuan; Liu, Zhu; Shapiro, Leland; Yang, Jun; Burton, Gregory F
• Is Part Of: Journal of leukocyte biology. Volume 98:Issue 6(2015)
• Page Start: 1027
• Page End: 1035
• Publication Date: 2015-07-23
• Subjects: clathrin-dependent endocytosis -- endosome -- lysosome -- HIV-1 -- NF-κB -- IκBα; Leucocytes -- Periodicals; Reticulo-endothelial system -- Periodicals; 571.96
• DOI: 10.1189/jlb.2A0515-209R
• Languages: English
• ISSNs: 0741-5400

Abstract

Abstract : Mechanism by which AAT entry into CD4 + T cells block NF-κB activation and HIV-1 replication. Abstract: In α1-antitrypsin–deficient HIV patients, an accelerated decline of CD4 + T cell numbers is observed, suggesting that α1-antitrypsin is a potential endogenous HIV inhibitor. In infected T lymphocytes, α1-antitrypsin potently blocks NF-κB activation and HIV-1 replication by directly interacting with IκBα in the cytosol, thereby altering its ubiquitination pattern. However, the mechanism of α1-antitrypsin entry into the cytosol, where IκBα locates, remains unclear. In the present study, we investigated the mechanism of α1-antitrypsin internalization in CD4 + T cells. Thus, primary CD4 + T cells were infected with HIV-1 and then incubated with α1-antitrypsin to detect its internalization. We found that CD4 + T cells internalized α1-antitrypsin through a clathrin-dependent endocytosis process. Next, intracellular α1-antitrypsin exerted the inhibitory effect on NF-κB activation and HIV-1 replication. On primary CD4 + T cells, α1-antitrypsin interacted with low-density lipoprotein receptor-related protein 1 to initiate the internalization. Inside CD4 + T lymphocytes, α1-antitrypsin was transported from the endosome to the lysosome and then released into the cytosol, where it is possible for α1-antitrypsin to directly interact with IκBα. These results together suggest that α1-antitrypsin internalization is a clathrin-dependent and low-density lipoprotein receptor-related protein 1–mediated endocytosis process. Internalized α1-antitrypsin is transported through the endosome–lysosome–cytosol routine to interact with cytosolic IκBα and block NF-κB activation and HIV-1 replication.