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Cytosolic detection of the bacterial metabolite HBP activates TIFA-dependent innate immunity

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Science  12 Jun 2015:
Vol. 348, Issue 6240, pp. 1251-1255
DOI: 10.1126/science.aaa4921

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Detecting Gramnegative bacteria

Invariant molecules specific to different classes of microbes, but not expressed by eukaryotic cells, alert the immune system to a potential invader. Gaudet et al. identified one such molecule expressed by a variety of Gram-negative bacteria: the monosaccharide heptose-1,7-bisphosphate (HBP) (see the Perspective by Brubaker and Monack). HBP is an intermediate in the synthesis of lipopolysaccharide, a major component of bacterial cell walls. Rather than alerting the immune system through traditional pathogen detection pathways, such as Toll-like receptors, HBP signals through the host protein TIFA (TRAF-interacting protein with forkhead-associated domain), which activates both innate and adaptive immune responses to control the infection.

Science, this issue p. 1251; see also p. 1207

Abstract

Host recognition of pathogen-associated molecular patterns (PAMPs) initiates an innate immune response that is critical for pathogen elimination and engagement of adaptive immunity. Here we show that mammalian cells can detect and respond to the bacterial-derived monosaccharide heptose-1,7-bisphosphate (HBP). A metabolic intermediate in lipopolysaccharide biosynthesis, HBP is highly conserved in Gram-negative bacteria, yet absent from eukaryotic cells. Detection of HBP within the host cytosol activated the nuclear factor κB pathway in vitro and induced innate and adaptive immune responses in vivo. Moreover, we used a genome-wide RNA interference screen to uncover an innate immune signaling axis, mediated by phosphorylation-dependent oligomerization of the TRAF-interacting protein with forkhead-associated domain (TIFA) that is triggered by HBP. Thus, HBP is a PAMP that activates TIFA-dependent immunity to Gram-negative bacteria.

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