Abstract
Legionella pneumophila extensively modulates the host ubiquitin network to create the Legionella-containing vacuole (LCV) for its replication. Many of its virulence factors function as ubiquitin ligases or deubiquitinases (DUBs). Here, we identify Lem27 as a DUB that displays a preference for diubiquitin formed by K6, K11, or K48. Lem27 is associated with the LCV where it regulates Rab10 ubiquitination in concert with SidC and SdcA, two bacterial E3 ubiquitin ligases. Structural analysis of the complex formed by an active fragment of Lem27 and the substrate-based suicide inhibitor ubiquitin-propargylamide (PA) reveals that it harbors a fold resembling those in the OTU1 DUB subfamily with a Cys-His catalytic dyad and that it recognizes ubiquitin via extensive hydrogen bonding at six contact sites. Our results establish Lem27 as a DUB that functions to regulate protein ubiquitination on L. pneumophila phagosomes by counteracting the activity of bacterial ubiquitin E3 ligases.
Highlights
The Gram negative bacterium Legionella pneumophila is an opportunistic pathogen ubiquitously found in natural and man-made water systems, often by association with amoebae species 1
To identify additional effectors that potentially harbor DUB activity, we analyzed Dot/Icm substrates 42,43 with HHpred 44 and found that Lem[27] contains a motif remotely resembling active sites associated with the ovarian tumor proteases (OTUs) superfamily of DUBs 36
We identified Lem[27] as an additional deubiquitinase, which adds to the complexity of the interference of the host ubiquitin network by L. pneumophila
Summary
The Gram negative bacterium Legionella pneumophila is an opportunistic pathogen ubiquitously found in natural and man-made water systems, often by association with amoebae species 1. The bacterial phagosome called the Legionella-containing vacuole (LCV) initiates a trafficking route that bypasses the endocytic maturation pathway endoplasmic reticulum (ER) and is eventually converted into a compartment whose membranes resemble those of the ER 4,5. Dot/Icm type IV secretion system of L. pneumophila 6. These virulence factors, called effectors,interfere with such diverse cellular processes as membrane trafficking, autophagy, protein translation and immunity by diverse mechanisms 7. The modulation of these processes is mediated by targeting key regulatory proteins via effector-induced posttranslational phosphorylcholination metabolism of lipids key in cell signaling[15], including the production of phosphatidylinositol-
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