The Autophagy Nucleation Factor ATG9 Forms Nanoclusters with the HIV-1 Receptor DC-SIGN and Regulates Early Antiviral Autophagy in Human Dendritic Cells

• Published in: International journal of molecular sciences Vol. 24; no. 10; p. 9008
• Main Authors: Papin, Laure, Lehmann, Martin, Lagisquet, Justine, Maarifi, Ghizlane, Robert-Hebmann, Véronique, Mariller, Christophe, Guerardel, Yann, Espert, Lucile, Haucke, Volker, Blanchet, Fabien P
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 19-05-2023; MDPI
• Subjects: Antibodies; Antigen presentation; Antigens; Antiviral agents; Antiviral Agents - metabolism; Autophagy; CD4 antigen; Cell activation; DC-SIGN; DC-SIGN protein; Dendritic Cells; Dendritic structure; Dengue fever; Disease transmission; Epithelial cells; Epithelium; Histograms; HIV; HIV (Viruses); HIV-1; HIV-1 - physiology; Human health and pathology; Human immunodeficiency virus; Humans; Immune system; Immunology; Infections; Infectious diseases; Innate immunity; Internalization; Lectins, C-Type - metabolism; Life Sciences; Ligands; Localization; Lymphocytes; Lymphocytes T; Microbiology and Parasitology; Monocytes; Nanoclusters; Pathogens; Pattern recognition; Resveratrol; Stimulated emission; T cells; Tuberculosis; Viral infections; Virology; United Kingdom; France; Massachusetts; Germany; HIV-1; autophagy; dendritic cells; innate immunity; DC-SIGN
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24109008

Dendritic cells (DC) are critical cellular mediators of host immunity, notably by expressing a broad panel of pattern recognition receptors. One of those receptors, the C-type lectin receptor DC-SIGN, was previously reported as a regulator of endo/lysosomal targeting through functional connections with the autophagy pathway. Here, we confirmed that DC-SIGN internalization intersects with LC3
autophagy structures in primary human monocyte-derived dendritic cells (MoDC). DC-SIGN engagement promoted autophagy flux which coincided with the recruitment of ATG-related factors. As such, the autophagy initiation factor ATG9 was found to be associated with DC-SIGN very early upon receptor engagement and required for an optimal DC-SIGN-mediated autophagy flux. The autophagy flux activation upon DC-SIGN engagement was recapitulated using engineered DC-SIGN-expressing epithelial cells in which ATG9 association with the receptor was also confirmed. Finally, Stimulated emission depletion (STED) microscopy performed in primary human MoDC revealed DC-SIGN-dependent submembrane nanoclusters formed with ATG9, which was required to degrade incoming viruses and further limit DC-mediated transmission of HIV-1 infection to CD4
T lymphocytes. Our study unveils a physical association between the Pattern Recognition Receptor DC-SIGN and essential components of the autophagy pathway contributing to early endocytic events and the host's antiviral immune response.