Dynamic interactions between autophagosomes and lysosomes are key to ensuring the trafficking of mycobacteria through the degradative autophagolysosomal pathway. Phosphoinositides (PtdIns), play critical roles in directing the trafficking of pathogens through phagosomal or autophagosomal degradation pathways. Phosphoinositide kinase, FYVE-type zinc finger containing, PIKfyve catalyzes the phosphorylation of PtdIns(3)P to PtdIns(3,5)P 2 . Generation of PtdIns(3,5)P 2 is critical for the maturation of autophagosomes and the proper functioning of lysosomes. The involvement of PIKfyve in immune defense against mycobacterial infections has not been addressed. Here, we studied the role of PIKfyve in Mycobacterium marinum ( Mm ) infection of zebrafish larvae using two chemical inhibitors of the enzymatic activity of PIKfyve, YM201636 and Apilimod. We demonstrate that PIKfyve is required for Mm -containing vesicle trafficking towards degradative lysosomes. We found that in the infected macrophages, PIKfyve facilitates autophagy pathway activation and (auto)phagosome maturation, and protects against cell death, thus boosting the host immune response against mycobacterial infection. This study links PIKfyve to the autolysosomal defense against a mycobacterial pathogen.
Muñoz‐Sánchez et al. (Wed,) studied this question.