Convergent evolution of a fungal effector enabling phagosome membrane penetration

The ability of pathogens to evade phagosomal killing is critical for their pathogenicity. Previously, we had identified the HscA effector protein in the clinically important fungal pathogen Aspergillus fumigatus, which redirects conidia-containing phagosomes from the degradative to the non-degradative pathway. Here, we discovered a pathogenic form of this surface protein, determined by a single tyrosine residue (Y) at position 596, which is lacking in most fungi analyzed, that have a leucine (L) instead. Y596 enables HscA to penetrate the phagosomal membrane. In line, the introduction of a single L- to-Y exchange in the orthologous Ssb protein of Saccharomyces cerevisiae enabled the protein to penetrate phagosomal membranes that was reduced by deletion of one of the two Y-encoding SSB genes in the pathogenic fungus Candida glabrata. These data suggest a convergent evolution of HscA/Ssb proteins among human-pathogenic fungi and that a single amino acid exchange determines a virulence factor. HighlightsO_LIHscA with Y596 penetrates host cell membranes and causes phagosomal damage C_LIO_LIMost fungi (96%) have a leucine at the respective position C_LIO_LIAn L-to-Y mutation in Ssb enables S. cerevisiae to damage phagosomes C_LIO_LIRecruitment of ESCRT complex to the phagosomal membrane requires human p11 protein C_LI