Aguirre-Garcia, M. A.; Portelli, S. M.; Varela, M.; Meijer, A.

Guanylate-binding proteins (GBPs) are a family of interferon-inducible proteins playing diverse roles in the immunity to infections. By docking onto pathogens or pathogen-containing vesicles, GBPs can boost proinflammatory signaling. However, the interplay between GBPs and the phagolysosomal mechanisms mediating pathogen degradation remains largely unclear. Here, we elucidate the key role of GBP1 in driving lysosomal activity against mycobacterial infection in human macrophages. We show that phagosome damage induced by the mycobacterial ESX-1 secretion system triggers calcium release, and thereby the recruitment of GBP1, which resides in lysosomes upon interferon gamma activation. GBP1 targeting of mycobacteria-containing phagosomes leads to the recruitment of other GBPs but does not lead to the activation of membrane repair mechanisms or antimicrobial autophagy. Instead, GBP1 mediates lysosomal recruitment to intracellular mycobacteria, and promotes the maturation of phagolysosomes and their proteolytic activity required for the degradation of the mycobacterial cargo. Collectively, this work highlights the host-protective function of GBP1 in macrophages, where GBP1 acts as a key cellular sensor of mycobacterial infection and promotes the clearance activity of the host lysosomal system.