ALPK1 (Alpha Kinase 1) is an atypical serine/threonine-protein kinase that specifically detects and binds the pathogen-associated pattern metabolites (PAMPs), ADP-beta-D-manno-heptose (Beta-ADP-Heptose) or D-glycero-beta-D-manno-heptose 1,7-bisphosphate (HBP). These metabolic precursors of lipopolysaccharide (LPS) biosynthesis are present in all Gram-negative and some Gram-positive bacteria. This interaction stimulates ALPK1 to phosphorylate and activate TIFA, initiating an innate immune response to perceived bacterial infection. The activated TIFA forms large complexes, known as TIFAsomes, in association with TAB2 and TRAF2 or 6 that, in turn, phosphorylate and activate TAK1. TAK1 subsequently activates NF-kappa beta to induce the expression of pro-inflammatory cytokines, such as TNF-alpha, IL-1 beta, IL-6, and IL-8.1
ALPK1 as Broad Sword
As a result of ALPK1-initiated signaling, massive neutrophil recruitment ensues, and defensive cytokines/chemokines/adhesion molecules are deployed against bacterial invaders. This is a localized diffusion of generalized anti-microbial elements designed to push back the invaders until a more specific adaptive response can arrive. While it serves to keep pathogens from advancing, it also causes regionalized inflammation in affected host tissues. This system is our first response to invading Neisseria, Yersinia, Salmonella, Shigella, and Helicobacter species. Longer-term and without appropriate moderation, such a response can result in more troubling issues.2
ALPK1 as Loose Cannon
Prolonged or particularly severe ALPK1-mediated inflammation in response to bacterial infection has been shown to produce unexpected consequences. The presence of Fusobacterium nucleatum in the flora of colon cancer patients facilitates metastasis by its abnormal stimulation of the ALPK1 pro-inflammatory pathway and ICAM1 synthesis. Patients harboring F. nucleatum exhibit markedly shorter metastasis-free survival time.3 Similarly, chronic Helicobacter pylori infection causes double-stranded DNA breaks in associated gastric epithelial cells via Beta-ADP-Heptose induced ALPK1/TIFA/NF-kappa beta signaling. This phenomenon is beginning to explain the complex path of gastric carcinogenesis: from focal inflammation to atrophy to dysplasia and transformation.4 In a similar vein, high ALPK1 expression facilitates the progression of oral squamous cell carcinoma.5 ALPK1 is also providing a new take on the possible origin of type 1 diabetes. Both the presence of Beta-ADP-Heptose AND potentiated ALPK1 cytokine signaling act synergistically to sensitize pancreatic beta cells to apoptosis.6
Even more insights into disease are coming from examples of somatic ALPK1 gene alterations. Missense variants in ALPK1 are now linked to the autosomal dominant inheritance of PFAPA Syndrome, characterized by periodic fever, canker sores, and inflammation of the oral cavity.7
Another autosomal dominant missense mutation in ALPK1, (c. 710C>T, [p.Thr237Met]), causes ROSAH Syndrome, characterized by retinal dystrophy, optic nerve swelling, enlarged spleen, the inability to sweat, and migraine headache. In certain patients, ROSAH may also include ectodermal dysplasia, causing oligodontia and sparse hair, and early onset arthritis. About half of these patients also suffer from cytopenia. While existing TNF-alpha and COX-2 inhibitors provided relief for some of these symptoms, they did not alleviate all of them.8
ALPK1 can be both a useful servant and a fearful master.
- Cong, Yingzi. (2018) ALPK1: A Pattern Recognition Receptor for Bacterial ADP-heptose. Precision Clinical Medicine, 1(2), 57-59. https://doi.org/10.1093/pcmedi/pby012
- Milivojevic, M. et al. (2017) ALPK1 Controls TIFA/TRAF 6-Dependent Innate Immunity Against Heptose-1,7 bisphosphate of Gram-negative Bacteria. PLOS Pathogens, 13(2), e1006224. https://doi.org/10.1371/journal.ppat.1006224
- Zhang, Y. et al. (2022) Fusobacterium nucleatum Promotes Colorectal Cancer Cells Adhesion to Endothelial Cells and Facilitates Extravasation and Metastasis by Inducing ALPK1/NF-κB/ICAM1 Axis. Gut Microbes, 14(1), e2038852. https://doi.org/10.1080/19490976.2022.2038852
- Zimmermann, S. et al. (2017) ALPK1- and TIFA-Dependent Innate Immune Response Triggered by the Helicobacter pylori Type IV Secretion System. Cell Reports, 20, 2384-2395. http://dx.doi.org/10.1016/j.celrep.2017.08.039
- Chen, P-K. et al. (2018) ALPK1 Expression Is Associated with Lymph Node Metastasis and Tumor Growth in Oral Squamous Cell Carcinoma Patients. The American Journal of Pathology, 189(1), 190-199. https://doi.org/10.1016/j.ajpath.2018.09.003
- Ding, F. et al. (2021) Alpk1 Sensitizes Pancreatic Beta Cells to Cytokine-Induced Apoptosis via Upregulating TNF-α Signaling Pathway. Frontiers in Immunology, 12, e705751. https://doi.org/10.3389/fimmu.2021.7057517.
- Sangiorgi, E et al. (2019) Rare Missense Variants in the ALPK1 Gene May Predispose to Periodic Fever, Aphthous Stomatitis, Pharyngitis and Adenitis (PFAPA) Syndrome. European Journal of Human Genetics, 27(9), 1361-1368. https://doi.org/10.1038/s41431-019-0421-6
- Hecker, J. et al. (2022) Early Onset of TNFα‑Driven Arthritis, Auto‑inflammation, and Progressive Loss of Vision in a Patient with ALPK1 Mutation. Journal of Clinical Immunology, Letter to Editor. https://doi.org/10.1007/s10875-022-01214-8