ATG5 provides host protection acting as a switch in the atg8ylation cascade between autophagy and secretion

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.

Automated summary

ATG5 is involved in the lipidation of ATG8 proteins, essential for membrane atg8ylation and autophagy. Loss of Atg5 in myeloid cells leads to early mortality in tuberculosis models. Absence of ATG5 promotes lysosomal exocytosis, secretion of extracellular vesicles, and excessive degranulation in neutrophils. This is due to lysosomal disrepair and sequestration of ALIX by an alternative conjugation complex, highlighting the importance of ATG5 in host protection and the branching aspects of atg8ylation beyond autophagy.