Low-density lipoprotein receptor-related protein 1 mediates α1-antitrypsin internalization in CD4+ T lymphocytes

Journal of Leukocyte Biology

Xueyuan Zhou, ¹  Zhu Liu¹  Jun Yang and¹  Leland Shapiro¹  Gregory F. Burton ¹ 

[1] 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

关键词: clathrin-dependent endocytosis;    endosome;    lysosome;    HIV-1;    NF-κB;    IκBα;   

DOI  :  10.1189/jlb.2A0515-209R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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.

【 授权许可】

Unknown