ATG5 provides host protection acting as a switch in the atg8ylation cascade between autophagy and secretion
- PMID: 37054706
- PMCID: PMC10205698
- DOI: 10.1016/j.devcel.2023.03.014
ATG5 provides host protection acting as a switch in the atg8ylation cascade between autophagy and secretion
Abstract
ATG5 is a part of the E3 ligase directing lipidation of ATG8 proteins, a process central to membrane atg8ylation and canonical autophagy. Loss of Atg5 in myeloid cells causes early mortality in murine models of tuberculosis. This in vivo phenotype is specific to ATG5. Here, we show using human cell lines that absence of ATG5, but not of other ATGs directing canonical autophagy, promotes lysosomal exocytosis and secretion of extracellular vesicles and, in murine Atg5fl/fl LysM-Cre neutrophils, their excessive degranulation. This is due to lysosomal disrepair in ATG5 knockout cells and the sequestration by an alternative conjugation complex, ATG12-ATG3, of ESCRT protein ALIX, which acts in membrane repair and exosome secretion. These findings reveal a previously undescribed function of ATG5 in its host-protective role in murine experimental models of tuberculosis and emphasize the significance of the branching aspects of the atg8ylation conjugation cascade beyond the canonical autophagy.
Keywords: ATG5; ESCRT; SARS-CoV-2; atg8ylation; autophagy; coronavirus; exosomes; lysosome; neutrophils; tuberculosis.
Copyright © 2023 Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of interests The authors declare no competing interests.
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