How the Legionella Effector SidL Modifies 3-Phosphoglycerate via Adenylyltransferase Activity

Highlights

  • •
    SidL is an actin-dependent adenylyltransferase that targets host glycolysis
  • •
    SidL adenylates 3PG to produce 2-AMP-3PG
  • •
    Expression of SidL in human cells disrupts glycolysis and blocks mTORC1 signaling
  • •
    Production of 2-AMP-3PG by SidL occurs early during the Legionella infection cycle


Summary

The large effector arsenal of the bacterial pathogen Legionella pneumophila has been a rich source of biochemistry, highlighting the immense diversity of strategies deployed in host-pathogen conflict. Here, we redefine the purported translation inhibitor SidL as an adenylyltransferase that targets a glycolytic metabolite, discovering that it modifies 3-phosphoglycerate with adenosine monophosphate (AMP) to produce the previously unknown molecule 2-AMP-3-phosphoglycerate. When expressed alone in mammalian cells, SidL adenylates 3-phosphoglycerate, disrupts glycolysis, and blocks the nutrient-responsive translation regulator mTORC1, which we propose indirectly causes translation inhibition. Moreover, we observe SidL-dependent production of 2-AMP-3-phosphoglycerate in macrophages during L. pneumophila infection, the timing of which is consistent with a role for SidL in the early stages of the infection cycle. Thus, our study uncovers a mechanism by which an intracellular pathogen uses the chemical modification of a glycolytic intermediate to target central carbon metabolism in the host.

Read full article for free (open access):
https://www.sciencedirect.com/science/article/pii/S1097276526004715



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