1. Heptose 1,7-Bisphosphate Directed TIFA Oligomerization: A Novel PAMP-Recognizing Signaling Platform in the Control of Bacterial Infections 
Kumar Pachathundikandi, Steffen Backert 
Gastroenterology 
Volume 154, Issue 4, Pages (March 2018)
DOI: /j.gastro
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2. Figure 1
The Gram-negative bacterial lipopolysaccharide (LPS) at the outer membrane gives a strong protection to the different challenges from the environment on transmission to the host and colonization. (A) LPS consists of a lipid-A portion, which strongly fixes the molecule to the bacterial membrane; an oligosaccharide core region; and a varied polysaccharide region on the outer side, which is involved in strain variation. In addition, LPS released from bacteria is the ligand for the innate immune response receptor, Toll-like receptor 4 (TLR4), as it detects the lipid-A portion of LPS. Recently, the inner core heptose moiety biosynthetic intermediate heptose 1,7 bisphosphate (HBP) was identified as a potential immunogen, which is sensed by tumor necrosis factor-α receptor–associated factor (TRAF)-interacting protein with forkhead-associated domain (TIFA) in the host cytoplasm. (B) The bacterial ADP-heptose pathway for the production of heptose moiety of the inner core of LPS. All the genes involved in this pathway are well-conserved in Gram-negative bacteria. HBP is produced at the third step of this pathway and actively released to the host cytoplasm at the logarithmic growth phase. (C) The chair structural form of HBP.
Gastroenterology  , DOI: ( /j.gastro )
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3. Figure 2
The role of heptose 1,7 bisphosphate (HBP) delivery and host cell signaling induced by Gram-negative bacteria. (A) HBP is delivered to the cytoplasm mainly by intracellular growth of pathogens such as Shigella flexneri and Salmonella enterica serovar Typhimurium. Extracellular Helicobacter pylori actively transfers HBP through the type IV secretion system (T4SS). However, actively secreted HBP or released after lysis of the bacterium Neisseria meningitidis seem to be delivered to the cytoplasm through the endocytotic route. HBP presence in the cytoplasm is sensed by tumor necrosis factor-α receptor–associated factor (TRAF)-interacting protein with forkhead-associated domain (TIFA). During infection, alpha kinase 1 (ALPK1)-induced TIFA Thr-9 phosphorylation leads to self-oligomerization. This process activates TRAF2/6 oligomerization and ubiquitination, and the recruitment of TAB2, with the inclusion of other host factors to trigger the activation of nuclear factor (NF)-κB. This complex was named recently as TIFAsome. TIFAsome-activated kinase TAK1 induces NF-κB nuclear translocation and proinflammatory gene expression. In addition, adjacent noninfected bystander cells also activated TIFAsome formation during S flexneri infection. The described mechanism helps to differentiate the actively growing bacteria inside the cytoplasm from stationary phase. (B) It can be postulated that there is no transfer of HBP into gut epithelial cells by the microbiota. This condition may lead to the prevention of TIFAsome activation or even its active inhibition, which results in the lack of an optimal innate immune responses by inactive NF-κB. Thus, the strict rule of HBP presence in the cytoplasm for TIFAsome activation could save the microbiota from proinflammatory attack, which may also help to maintain homeostasis in the gut.
Gastroenterology  , DOI: ( /j.gastro )
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