Legionella pneumophila uses a type IV secretion system to inject >100 effectors into the host cell in order to coordinate cellular processes such as membrane trafficking to the vacuole in which the bacterium replicates, innate immune responses and bacterial egress following repli­cation. Although the biochemical function of most of these effectors is unknown, strict spatiotemporal regu­lation of their activity is likely to be required for the modulation of dis­tinct host cell functions at different stages of infection. Writing in PLoS Pathogens, Kubori et al. describe for the first time a bacterial ‘meta­effector’: an effector that acts directly on another effector to modulate its function inside the host cell.

The effector, LubX, is a member of the U­box family of E3 ubiquitin ligases and has previously been shown to polyubiquitylate the host cell kinase CLK1. To further charac­terize the role of LubX, Kubori et al. investigated other putative effectors that are encoded in close proximity to lubX. By making fusions between these effectors and an adenylate cyclase (Cya) reporter and then mon­itoring the production of cyclic AMP in the host cell, the authors assayed secretion of these putative effectors in wild type and lubX mutants. Surprisingly, for one of these fusion proteins, Cya–SidH, they observed that cAMP levels were substantially lower in cells infected with wild­type

L. pneumophila than in cells infected with an isogenic lubX­mutant strain, indicating that the loss of LubX correlates with increased levels of Cya–SidH in the host cell. Treatment with the proteasome inhibitor MG132 resulted in similar levels of Cya–SidH in cells infected with either the wild type or the lubX mutant, suggesting that the effect of LubX on Cya–SidH may involve its ubiquitin ligase activity. Supporting this notion, the authors observed a direct interaction between

recombinant SidH and LubX and found that SidH could be poly­ubiquitylated in vitro and in vivo in a LubX­dependent manner.

LubX expression is only induced during host cell infection, with levels increasing gradually before peaking ~10 hours after infection. By contrast, SidH is expressed prior to infection and its levels only start to decrease in infected cells following LubX expression, suggesting that the temporally regulated expression of LubX can control the level of SidH found in the host cell. Finally, using a Drosophila melanogaster infection system, the authors found that lubX mutants exhibited hyper­lethality to the insect host compared with the lethality of wild type or sidH mutants, despite consistently lower viable lubX-mutant cell counts, indicating that the prolonged presence of SidH is both toxic to the host cell and detrimental to the growth of the infecting bacterium.

Effectors with E3 ubiquitin ligase activity are prevalent among plant and bacterial pathogens. In light of these findings, it will be interesting to see how many of these effectors act as meta­effectors by targeting other pathogen proteins for degradation.

Andrew Jermy

b ac t e r i a l Pat H O G e N e S i S

Legionella effector under friendly fire

meta-effector: an effector that acts directly on another effector to modulate its function inside the host cell

OriGiNal reSearcH PaPer Kubori, T. et al. Legionella metaeffector exploits host proteasome to temporally regulate cognate effector. PLoS Pathog. 6, e1001216 (2010)

R e s e a R c h h i g h l i g h t s

nATUrE rEVIEWS | Microbiology VoLUME 9 | FEBrUAry 2011

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