ADP-heptose: a bacterial PAMP detected by the host sensor ALPK1

Abstract

The innate immune response constitutes the first line of defense against pathogens. It involves the recognition of pathogen-associated molecular patterns (PAMPs) by pathogen recognition receptors (PRRs), the production of inflammatory cytokines and the recruitment of immune cells to infection sites. Recently, ADP-heptose, a soluble intermediate of the lipopolysaccharide biosynthetic pathway in Gram-negative bacteria, has been identified by several research groups as a PAMP. Here, we recapitulate the evidence that led to this identification and discuss the controversy over the immunogenic properties of heptose 1,7-bisphosphate (HBP), another bacterial heptose previously defined as an activator of innate immunity. Then, we describe the mechanism of ADP-heptose sensing by alpha-protein kinase 1 (ALPK1) and its downstream signaling pathway that involves the proteins TIFA and TRAF6 and induces the activation of NF-κB and the secretion of inflammatory cytokines. Finally, we discuss possible delivery mechanisms of ADP-heptose in cells during infection, and propose new lines of thinking to further explore the roles of the ADP-heptose/ALPK1/TIFA axis in infections and its potential implication in the control of intestinal homeostasis.

Keywords: ADP-heptose; ALPK1; Bacterial infection; Innate immunity; PAMP; TIFA.

Fig. 1

a Smooth, rough and deep-rough lipopolysaccharide (LPS) structures of a prototypical Gram-negative bacterium. The lipid A, the inner and outer core, and the O-antigen structures are depicted. P phosphate, Hep heptose, GlcN N-acteyl-glucosamine, Kdo 3-deoxy-d-manno-oct-2-ulosonic acid. b Schematic representation of the enzymes (in red) and metabolites (in black) involved in the inner-core lipopolysaccharide biosynthesis pathway. The heptoses that possess immunogenic properties are highlighted in blue (HBP), gray (HMP1) and purple (ADP-DD-heptose and ADP-LD-heptose). The enzymes present in Neisseria species are shown in brackets

Fig. 2

a Schematic representation of the structure of inactive TIFA as an intrinsic dimer. Note the threonine 9, the FHA domain with its pT9 recognizing domain and the E178 residue responsible for TRAF6 binding. b Schematic representation of TIFAsome formation upon threonine 9 phosphorylation. Note that TRAF6 oligomerization is responsible for NF-κB activation (Adapted from Huang et al. 2012). c Fluorescence microscopy images of HeLa cells transfected with a TIFA-GFP encoding plasmid stimulated or not with ADP-heptose. Cell nuclei are shown in blue, TIFA-GFP in green. Scale bar 20 µm. d Schematic representation of ALPK1 activation upon ADP-heptose recognition

Fig. 3

a Schematic representation of direct ADP-heptose-dependent (black bold arrows) and indirect HBP-dependent (gray dotted arrows) ALPK1 activation, leading to TIFA phosphorylation and oligomerization. b Schematic representation of the activation of the ADP-heptose/ALPK1/TIFA/TRAF6/NF-κB pathway resulting in pro-inflammatory cytokine release and neutrophil recruitment. c Schematic representation of the possible delivery mechanisms of ADP-heptose during infection by Shigella, Neisseria, Yersinia and Helicobacter bacteria