VipD is a Rab5-activated phospholipase A1 that protects Legionella pneumophila from endosomal fusion.

Abstract

A crucial step in the elimination of invading microbes by macrophages is phagosomal maturation through heterotypic endosomal fusion. This process is controlled by the guanine nucleotide binding protein Rab5, which assembles protein microdomains that include the tethering protein early endosomal antigen (EEA) 1 and the phosphatidylinositol (PI) 3-kinase hVps34, which generates PI(3)P, a phospholipid required for membrane association of EEA1 and other fusion factors. During infection of macrophages, the pathogen Legionella pneumophila bypasses the microbicidal endosomal compartment by an unknown mechanism. Here, we show that the effector protein VipD from L. pneumophila exhibits phospholipase A1 activity that is activated only upon binding to endosomal Rab5 or Rab22. Within mammalian cells, VipD localizes to endosomes and catalyzes the removal of PI(3)P from endosomal membranes. EEA1 and other transport and fusion factors are consequently depleted from endosomes, rendering them fusion-incompetent. During host cell infection, VipD reduces exposure of L. pneumophila to the endosomal compartment and protects their surrounding vacuoles from acquiring Rab5. Thus, by catalyzing PI(3)P depletion in a Rab5-dependent manner, VipD alters the protein composition of endosomes thereby blocking fusion with Legionella-containing vacuoles.