VipD is a Rab5-activated phospholipase A 1 that protects Legionella pneumophila from endosomal fusion
Significance The pathogen Legionella pneumophila replicates within human alveolar macrophages, causing a potentially fatal pneumonia known as Legionnaires’ disease. We identified that the effector protein VipD, which is injected into infected cells by L. pneumophila , localizes to degradative host o...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 12; pp. 4560 - 4565 |
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Main Authors | , |
Format | Journal Article |
Language | English |
Published |
25.03.2014
|
Online Access | Get full text |
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Summary: | Significance
The pathogen
Legionella pneumophila
replicates within human alveolar macrophages, causing a potentially fatal pneumonia known as Legionnaires’ disease. We identified that the effector protein VipD, which is injected into infected cells by
L. pneumophila
, localizes to degradative host organelles called endosomes. There, VipD binds to the endosomal regulator Rab5, an event that triggers the hydrolytic phospholipase A
1
activity in VipD, which causes the removal of the lipid phosphatidylinositol 3-phosphate. Without this key lipid, endosomes can no longer execute their function and
L. pneumophila
is protected from their harmful effect. Our finding opens new avenues for the development of therapeutics that interfere with the activation of VipD and with endosomal avoidance by
L. pneumophila
.
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 A
1
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. |
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ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.1316376111 |