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Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic γ-herpesvirus. Autophagy during KSHV entry has remained unexplored. We show that LC3 lipidation as a hallmark of autophagy is induced shortly after KSHV entry. LC3 co-localizes with KSHV in amphisomes during entry and loss of LC3 lipidation increases infection. Accordingly, NDP52, a receptor of selective autophagy, was recruited to endocytosed viral particles, and its reduction increased KSHV infection. Additionally, virus particles co-localized with the endolysosome damage sensor galectin-8 upon KSHV entry and depletion of galectin-8 promoted KSHV infection. Compared with herpes simplex virus, listeriolysin, adenovirus, and influenza virus, and in contrast to what was previously thought about enveloped viruses, KSHV binding to EphA2 by its envelope protein gH causes endolysosomal membrane damage, akin to non-enveloped viruses and bacteria. Taken together, our study identifies an important anti-viral role for galectin-8, NDP52, and the autophagy machinery at virus-damaged endosomes, restricting KSHV entry by selective autophagy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

LC3-associated phagocytosis (LAP) is an unconventional form of autophagy that relies on parts of the canonical autophagy machinery for its function. LAP is triggered upon receptor-mediated phagocytosis and is characterized by the formation of a single-membrane vesicle decorated with the autophagy protein LC3. In professional phagocytic cells, such as macrophages, the role of LAP in immune processes has been characterized, although how LAP functions at the molecular level remains poorly defined. It is important to point out that as for all autophagic pathways, the study of LAP is still challenging for the scientific community because it is a dynamic and complex process, requiring interactions among several proteins. Here, we describe the most common methods used to monitor and quantify the formation of LC3-coated single-membrane endosomes, or so-called LAPosomes, and to validate the involvement of LAP in immunological processes of human macrophages. © 2018 by John Wiley & Sons, Inc., (© 2018 John Wiley & Sons, Inc.)