ADP-heptose: A new innate immune modulator

Hu, Xiao; Yang, Chunhua; Wang, Peng George; Zhang, Gaolan

doi:10.1016/j.carres.2018.12.011

Cited by 16 publications

(15 citation statements)

References 53 publications

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“…These studies revealed ten cytokine deficiency-induced colitis susceptibility (Cdcs) loci and candidate genes with a potential influence on colitis onset [4][5][6][7][8][9]. One of these genes is Cd14 (Cluster of differentiation 14) in the Cdcs6 locus located on chromosome 18 [7]. CD14 acts as a coreceptor of Toll-like receptor (TLR) 4 and is directly involved in the detection of lipopolysaccharide (LPS) and activation of NF-κB [10].…”

Section: Introductionmentioning

confidence: 99%

“…Knockout of the Alpk1 gene in mice was recently shown to lead to severe colitis when infected with Helicobacter hepaticus [13]. ALPK1 functions as a pattern recognition receptor for adenosine diphosphateheptose (ADP-Hep), a precursor of LPS [14]. In human epithelial cells, ADP-Hep of Gram-negative bacteria activates NF-κB-dependent inflammatory interleukin-8 (IL-8) secretion via an ALPK1-TIFA-TRAF6 axis [15].…”

Section: Introductionmentioning

confidence: 99%

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CD14 and ALPK1 Affect Expression of Tight Junction Components and Proinflammatory Mediators upon Bacterial Stimulation in a Colonic 3D Organoid Model

Brooks

Bruegge

Boyle

et al. 2020

Stem Cells International

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Cd14 and Alpk1 both encode pathogen recognition receptors and are known candidate genes for affecting severity in inflammatory bowel diseases. CD14 acts as a coreceptor for bacterial lipopolysaccharide (LPS), while ALPK1 senses ADP-D-glycero-beta-D-manno-heptose, a metabolic intermediate of LPS biosynthesis. Intestinal barrier integrity can be influenced by CD14, whereas to date, the role of ALPK1 in maintaining barrier function remains unknown. We used colon-derived 3D organoids, first characterised for growth, proliferation, stem cell markers, and expression of tight junction (TJ) components using qPCR and immunohistochemistry. They showed characteristic crypt stem cells, apical shedding of dead cells, and TJ formation. Afterwards, organoids of different genotypes (WT, Il10-/-, Cd14-/-, and Alpk1-/-) were then stimulated with either LPS or Escherichia coli Nissle 1917 (EcN). Gene expression and protein levels of cytokines and TJ components were analysed. WT organoids increased expression of Tnfα and tight junction components. Cd14-/- organoids expressed significantly less Tnfα and Ocln after LPS stimulation than WT organoids but reacted similarly to WT organoids after EcN stimulation. In contrast, compared to WT, Alpk1-/- organoids showed decreased expression of different TJ and cytokine genes in response to EcN but not LPS. However, Western blotting revealed an effect of ALPK1 on TJ protein levels. These findings demonstrate that Cd14, but not Alpk1, alters the response to LPS stimulation in colonic epithelial cells, whereas Alpk1 is involved in the response upon bacterial challenge.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CD14 and ALPK1 Affect Expression of Tight Junction Components and Proinflammatory Mediators upon Bacterial Stimulation in a Colonic 3D Organoid Model

Brooks

Bruegge

Boyle

et al. 2020

Stem Cells International

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“…As is well known, Gram-negative bacterium is a rich source of heptose motifs, which can participate in bacterial colonization, infection, and immune recognition (Hu et al, 2019). Both ADP-and GDP-heptoses that participate the installation of polysaccharides like CPS and LPS are biosynthesized via a similar process involving four enzymes, an isomerase, a kinase, a phosphatase, and a nucleotidyltransferase (Valvano et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…They are also involved in the biosynthesis of a number of heptose-containing natural products from Gram-positive bacteria (Tang et al, 2018;. ADP-D-glycero-β-D-manno-heptose is a common intermediate of those ADP-heptoses and its bio-synthesis has been extensively studied in Gram-negative bacterium (Hu et al, 2019;Kneidinger et al, 2002;Morrison and Tanner, 2007). In Burkholderia pseudomallei, the formation mechanism of ADP-D-glycero-β-D-manno-heptose is analogous to that of GDP-D-glycero-α-D-manno-heptose, which also converts S7-P to D-glycero-D-manno-heptose 7phosphate as the first intermediate, but differs in the following three steps: (i) the kinase HldA catalyzes the phosphorylation of the anomer carbon with a β-configuration; (ii) the phosphatase GmhB β is prone to recognize β-configured 1,7-diphosphate heptose; (iii) the nucleotidyltransferase HldC activates D-glycero-β-D-manno-heptose 1-phosphate as an ADP-sugar (Figure 1A and B) (Park et al, 2018;Lee et al, 2013;Wang et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

A conservative distribution of tridomain NDP-heptose synthetases in actinobacteria

Tang

Wang

et al. 2021

Sci. China Life Sci.

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Heptoses are important structural components of Gram-negative bacterium cell wall and participate in bacterial colonization, infection, and immune recognition. Current knowledge of NDP-heptose originating from d -sedoheptulose 7-phosphate in Grampositive bacterium remains limited. Here, in silico analysis suggested that the special tridomain NDP-heptose synthetases with isomerase, kinase, and nucleotidyltransferase activities are conservatively distributed in Actinobacteria class of Gram-positive bacterium. Enzymatical characterization of the tridomain proteins from different strains showed that they are involved in ADP- d - glycero-β - d - manno -heptose biosynthesis despite the unexpected discovery of kinase activities deficient in some proteins. The presence of three types of NDP-heptose synthetases in Gram-positive bacterium suggests that it is also a rich source of heptoses and the heptose moieties may play important roles in vivo . Our work updates the understanding of NDP-heptose biosynthesis in Gram-positive bacterium and lays a solid foundation for further physiological function explorations. Supporting Information The supporting information is available online at 10.1007/s11427-021-2000-2. The supporting materials are published as submitted, without typesetting or editing. The responsibility for scientific accuracy and content remains entirely with the authors.

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“…ADP heptose is an intermediate for the biogenesis of LPS in gram negative bacteria ( 34 ). In this study we used a synthesized ADP heptose to investigate the effects of Alpk1 activation on beta cell death in vitro .…”

Section: Discussionmentioning

confidence: 99%

Alpk1 Sensitizes Pancreatic Beta Cells to Cytokine-Induced Apoptosis via Upregulating TNF-α Signaling Pathway

Ding

Luo

et al. 2021

Front. Immunol.

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Pancreatic beta cell failure is the hallmark of type 1 diabetes (T1D). Recent studies have suggested that pathogen recognizing receptors (PRRs) are involved in the survival, proliferation and function of pancreatic beta cells. So far, little is known about the role of alpha-protein kinase 1 (ALPK1), a newly identified cytosolic PRR specific for ADP-β-D-manno-heptose (ADP-heptose), in beta cell survival. In current study we aimed to fill the knowledge gap by investigating the role of Alpk1 in the apoptosis of MIN6 cells, a murine pancreatic beta cell line. We found that the expression of Alpk1 was significantly elevated in MIN6 cells exposed to pro-inflammatory cytokines, but not to streptozotocin, low-dose or high-dose glucose. Activation of Alpk1 by ADP heptose alone was insufficient to induce beta cell apoptosis. However, it significantly exacerbated cytokine-induced apoptosis in MIN6 cells. Mechanistic investigations showed that Alpk1 activation was potent to further induce the expression of tumor necrosis factor (TNF)-α and Fas after cytokine stimulation, possibly due to enhanced activation of the TIFA/TAK1/NF-κB signaling axis. Treatment of GLP-1 receptor agonist decreased the expression of TNF-α and Fas and improved the survival of beta cells exposed to pro-inflammatory cytokines and ADP heptose. In summary, our data suggest that Alpk1 sensitizes beta cells to cytokine-induced apoptosis by potentiating TNF-α signaling pathway, which may provide novel insight into beta cell failure and T1D development.

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ADP-heptose: A new innate immune modulator

Cited by 16 publications

References 53 publications

CD14 and ALPK1 Affect Expression of Tight Junction Components and Proinflammatory Mediators upon Bacterial Stimulation in a Colonic 3D Organoid Model

CD14 and ALPK1 Affect Expression of Tight Junction Components and Proinflammatory Mediators upon Bacterial Stimulation in a Colonic 3D Organoid Model

A conservative distribution of tridomain NDP-heptose synthetases in actinobacteria

Alpk1 Sensitizes Pancreatic Beta Cells to Cytokine-Induced Apoptosis via Upregulating TNF-α Signaling Pathway

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