Akbar et al. reveal that the fly homologue of a gene mutated in human disease encodes a protein required for phagosome maturation and digestion of pathogens.

The HOPS complex is a multi-subunit tethering factor that regulates vacuole fusion in budding yeast. Metazoans express two versions of the HOPS subunits Vps16p and Vps33p. Vps16A and Vps33A promote the delivery of endosomes and autophagosomes to lysosomes in flies. The function of Vps16B and Vps33B is less clear, but mutations in the human homologues of these proteins cause a fatal multisystem disease called arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome.

Akbar et al. generated flies lacking Vps16B and found that they were surprisingly healthy and had no defects in autophagosome or endocytic trafficking. Knowing that ARC syndrome patients are susceptible to recurrent bacterial infections, however, the researchers injected the flies with E. coli and found that Vps16B mutants died much faster than wild-type strains. Mutant fly macrophages engulfed the bacteria normally but failed to digest them, as phagosomes failed to fully mature and fuse with lysosomes. This caused the bacteria to accumulate in intermediate phagocytic compartments, prompting Akbar et al. to name the Drosophila Vps16B gene full-of-bacteria. Similar effects were seen after knocking down Vps33B in flies.

It remains to be seen whether human Vps16B and Vps33B also control phagosome maturation and whether defects in this process account for other symptoms of ARC syndrome. Senior author Helmut Krämer now wants to investigate how the different HOPS subunit homologues contribute to distinct trafficking pathways.

et al
J. Cell Biol.