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Galectin-3 promotes HIV-1 budding via association with Alix and Gag p6

Significance Statement  

Human immunodeficiency virus (HIV) propagation requires the assistance of host cell factors at all stages of the infection cycle. HIV-1 Gag p6 protein contains the late domains, which can interact with Alix and Tsg101 (proteins associated with ESCRT) to facilitate viral budding. Galectin-3, a β-glycoside-binding lectin, has been reported to play a role in regulation of various cellular and immune responses. Other galectins, including galectin-1 and -9, have been shown to promote or attenuate viral infection through interaction of their carbohydrate-binding domains with both host and viral surface glycans. In this study, our data indicate that endogenous galectin-3 exhibits an intracellular function independent of its carbohydrate-binding activity in promoting HIV-1 budding by enhancing the interaction between Alix and Gag. In addition, we observed that galectin-3 is present within the HIV-1 virions released from galectin-3-expressing cells. We conclude that galectin-3 is dependent on Alix to promote HIV-1 budding. Inhibitors of galectin-3-Alix interaction may be employed as anti-HIV-1 agents.

Highlights

1. Endogenous galectin-3 expression enhances HIV-1 budding.

2. Galectin-3 is expressed in HIV-1 virions.

3. Galectin-3 associates with Alix and enhances the stabilization of Alix-Gag interaction.

4. Galectin-3 is dependent on Alix to promote HIV-1 budding.

Funding: This work was supported by grants from the Republic of China National Science Council (NSC 101-2320-B-001-015-MY2) and the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS RO1 AR056343).

Figure Legend: Summary of the mechanism of galectin-3 promoting HIV-1 budding

Galectin-3 promotes HIV-1 budding via association with Alix and Gag p6

 

 

 

 

 

 

 

 

Journal Reference

 

Wang SF1, Tsao CH2, Lin YT3, Hsu DK4, Chiang ML2, Lo CH2, Chien FC5, Chen P6, Arthur Chen YM7, Chen HY8, Liu FT8.

Glycobiology. 2014 Nov;24(11):1022-35.

Show Affiliations

1Department of Medical Laboratory Science and Biotechnology Institute of Biomedical Sciences Center for AIDS Prevention and Research.and

2Institute of Biomedical Sciences.and

3Center for AIDS Prevention and Research.and

4Institute of Biomedical Sciences Department of Dermatology, University of California at Davis, Davis, USA.and

5Department of Optics and Photonics, National Central University, Chung-Li, Taiwan.and

6Research Center for Applied Sciences, Academia Sinica, Taipei, Taiwan.and

7Department of Microbiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Center for AIDS Prevention and Research Department of Microbiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan [email protected] [email protected] [email protected]

8Institute of Biomedical Sciences Department of Dermatology, University of California at Davis, Davis, USA [email protected] [email protected] [email protected]

Abstract

Galectin-3 has been reported to regulate the functions of a number of immune cell types. We previously reported that galectin-3 is translocated to immunological synapses in T cells upon T-cell receptor engagement, where it associates with ALG-2-interacting protein X (Alix). Alix is known to coordinate with the endosomal sorting complex required for transport (ESCRT) to promote human immuno-deficiency virus (HIV)-1 virion release. We hypothesized that galectin-3 plays a role in HIV-1 viral budding. Cotransfection of cells of the Jurkat T line with galectin-3 and HIV-1 plasmids resulted in increased HIV-1 budding, and suppression of galectin-3 expression by RNAi in Hut78 and primary CD4+ T cells led to reduced HIV-1 budding. We used immunofluorescence microscopy to observe the partial colocalization of galectin-3, Alix and Gag in HIV-1-infected cells. Results from co-immunoprecipitation experiments indicate that galectin-3 expression promotes Alix-Gag p6 association, whereas the results of Alix knockdown suggest that galectin-3 promotes HIV-1 budding through Alix. HIV-1 particles released from galectin-3-expressing cells acquire thegalectin-3 protein in an Alix-dependent manner, with proteins primarily residing inside the virions. We also found that the galectin-3 N-terminal domain interacts with the proline-rich region of Alix. Collectively, these results suggest that endogenous galectin-3 facilitates HIV-1 budding by promoting theAlix-Gag p6  association.

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