title: Low-density lipoprotein receptor-related protein 1 mediates α1-antitrypsin internalization in CD4+ T lymphocytes.
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.
authors.affiliation: *Clinic Services Program, Leidos Biomedical Research Inc., Frederick, Maryland, USA; Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah, USA; Hainan Key Laboratory for Sustainable Utilization of Tropical Bioresources, College of Agriculture, Hainan University, Haikou, Hainan, China; Denver Veterans Affairs Medical Center, University of Colorado Denver, Denver, Colorado, USA; and Division of Infectious Diseases, Department of Medicine, University of Colorado Denver, Denver, Colorado, USA xueyuan.zhou@nih.gov zhuliu@hainu.edu.cn.
authors.forename: Xueyuan
authors.initials: X
authors.lastname: Zhou
authors.affiliation: *Clinic Services Program, Leidos Biomedical Research Inc., Frederick, Maryland, USA; Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah, USA; Hainan Key Laboratory for Sustainable Utilization of Tropical Bioresources, College of Agriculture, Hainan University, Haikou, Hainan, China; Denver Veterans Affairs Medical Center, University of Colorado Denver, Denver, Colorado, USA; and Division of Infectious Diseases, Department of Medicine, University of Colorado Denver, Denver, Colorado, USA xueyuan.zhou@nih.gov zhuliu@hainu.edu.cn.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Liu
authors.affiliation: *Clinic Services Program, Leidos Biomedical Research Inc., Frederick, Maryland, USA; Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah, USA; Hainan Key Laboratory for Sustainable Utilization of Tropical Bioresources, College of Agriculture, Hainan University, Haikou, Hainan, China; Denver Veterans Affairs Medical Center, University of Colorado Denver, Denver, Colorado, USA; and Division of Infectious Diseases, Department of Medicine, University of Colorado Denver, Denver, Colorado, USA.
authors.forename: Leland
authors.initials: L
authors.lastname: Shapiro
authors.affiliation: *Clinic Services Program, Leidos Biomedical Research Inc., Frederick, Maryland, USA; Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah, USA; Hainan Key Laboratory for Sustainable Utilization of Tropical Bioresources, College of Agriculture, Hainan University, Haikou, Hainan, China; Denver Veterans Affairs Medical Center, University of Colorado Denver, Denver, Colorado, USA; and Division of Infectious Diseases, Department of Medicine, University of Colorado Denver, Denver, Colorado, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: *Clinic Services Program, Leidos Biomedical Research Inc., Frederick, Maryland, USA; Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah, USA; Hainan Key Laboratory for Sustainable Utilization of Tropical Bioresources, College of Agriculture, Hainan University, Haikou, Hainan, China; Denver Veterans Affairs Medical Center, University of Colorado Denver, Denver, Colorado, USA; and Division of Infectious Diseases, Department of Medicine, University of Colorado Denver, Denver, Colorado, USA.
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Burton
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002966:Clathrin / Q000276:immunology; D003600:Cytosol / Q000276:immunology; D004705:Endocytosis / Q000276:immunology; D011992:Endosomes / Q000276:immunology; D005260:Female; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000276:immunology*; D008247:Lysosomes / Q000276:immunology; D008297:Male; D016328:NF-kappa B / Q000276:immunology; D014775:Virus Activation / Q000276:immunology*; D000515:alpha 1-Antitrypsin / Q000276:immunology*
chemical_list: D002966:Clathrin; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D016328:NF-kappa B; D000515:alpha 1-Antitrypsin
keywords: HIV-1; IκBα; NF-κB; clathrin-dependent endocytosis; endosome; lysosome