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Autophagy Proteins in the Restriction of Kaposi Sarcoma-Associated Herpesvirus Entry


Schmidt, Katarina Wendy. Autophagy Proteins in the Restriction of Kaposi Sarcoma-Associated Herpesvirus Entry. 2024, University of Zurich, Faculty of Science.

Abstract

When microorganisms invade host cells and access the cytoplasm, host defense mechanisms are deployed to direct pathogens to degradation by selective autophagy. Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic ɣ-herpesvirus associated with several opportunistic malignancies, including the fourth most common cancer in sub-Saharan Africa, Kaposi sarcoma. Numerous studies have investigated autophagy upon lytic reactivation of KSHV, however autophagy involvement in KSHV entry has remained unexplored. Using in vitro infection of human epithelial cell lines, we show that lipidation of the autophagy hallmark LC3 is induced shortly after KSHV entry. When components of the LC3 lipidation complex were depleted, infection increased. Accordingly, nuclear dot protein 52 kDa (NDP52), a receptor of selective autophagy, was recruited to endocytosed viral particles, and its reduction increased KSHV infection. Additionally, virus particles co-localized with both NDP52 and the endolysosome damage sensor galectin-8 upon KSHV entry and depletion of galectin-8 promoted KSHV infection. Using herpes simplex virus, listeriolysin, adenovirus and influenza virus as references, the KSHV data here reveal that, in contrast to what was previously thought about enveloped viruses, KSHV binding to EphA2 by its envelope protein gH could cause endolysosomal membrane damage, akin to non-enveloped viruses and bacteria. Taken together, our study identifies an important antiviral role for galectin-8 in the host cell-autonomous immune response to KSHV infection by recruitment of NDP52 and the autophagy machinery to virus-damaged endosomes. The resulting selective autophagy seems to restrict KSHV entry.

Abstract

When microorganisms invade host cells and access the cytoplasm, host defense mechanisms are deployed to direct pathogens to degradation by selective autophagy. Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic ɣ-herpesvirus associated with several opportunistic malignancies, including the fourth most common cancer in sub-Saharan Africa, Kaposi sarcoma. Numerous studies have investigated autophagy upon lytic reactivation of KSHV, however autophagy involvement in KSHV entry has remained unexplored. Using in vitro infection of human epithelial cell lines, we show that lipidation of the autophagy hallmark LC3 is induced shortly after KSHV entry. When components of the LC3 lipidation complex were depleted, infection increased. Accordingly, nuclear dot protein 52 kDa (NDP52), a receptor of selective autophagy, was recruited to endocytosed viral particles, and its reduction increased KSHV infection. Additionally, virus particles co-localized with both NDP52 and the endolysosome damage sensor galectin-8 upon KSHV entry and depletion of galectin-8 promoted KSHV infection. Using herpes simplex virus, listeriolysin, adenovirus and influenza virus as references, the KSHV data here reveal that, in contrast to what was previously thought about enveloped viruses, KSHV binding to EphA2 by its envelope protein gH could cause endolysosomal membrane damage, akin to non-enveloped viruses and bacteria. Taken together, our study identifies an important antiviral role for galectin-8 in the host cell-autonomous immune response to KSHV infection by recruitment of NDP52 and the autophagy machinery to virus-damaged endosomes. The resulting selective autophagy seems to restrict KSHV entry.

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Additional indexing

Item Type:Dissertation (monographical)
Referees:Münz Christian, Stertz Silke, Jung Jae
Communities & Collections:04 Faculty of Medicine > Institute of Experimental Immunology
UZH Dissertations
Dewey Decimal Classification:610 Medicine & health
570 Life sciences; biology
Language:English
Place of Publication:Zürich
Date:14 May 2024
Deposited On:14 May 2024 12:36
Last Modified:14 May 2024 12:42
Number of Pages:111
OA Status:Closed