Fig 1.
Host recognition of the bacterial metabolite HBP.
(A) Gram-negative bacteria possess a unique branch from the pentose phosphate pathway (PPP) that generates ADP- heptose precursors (ADP-hep) for incorporation of heptose (green hexagon) into the inner core of the LPS structure. Hep-1,7-PP (HBP) is synthesized in the second step of this pathway and is released from bacteria during growth or lysis. (B) Summary of the manners by which gram-negative bacteria can present HBP to mammalian cells and activate the TIFA-signaling pathway. TIFA is an intrinsic anti-parallel dimer, possessing a Threonine residue (Thr9), a central forkhead domain (FHA), and a C-terminal TRAF6 binding site (T6BP; green rectangle). Upon HBP detection, Thr9 is phosphorylated, driving head-to tail oligomerization via intermolecular pThr9-FHA interactions. TIFA oligomers or the ‘TIFAsome’ recruits and activates TRAF6, driving canonical NF-κB activation and inflammatory signaling. Inset fluorescence micrograph depicts HBP-induced TIFAsome formation (green, white arrow) in human colonic epithelial cells treated with HBP for 2 hours. Nucleus is stained with DAPI (blue), scale bar 5 μm.