Affinage

ALPK1

Alpha-protein kinase 1 · UniProt Q96QP1

Length
1244 aa
Mass
138.9 kDa
Annotated
2026-06-09
60 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ALPK1 is a cytosolic atypical (alpha-kinase) pattern recognition receptor that detects the bacterial ADP-heptose/heptose-bisphosphate metabolites generated during Gram-negative LPS biosynthesis and converts this sensing into NF-κB-driven innate immune signaling (PMID:28877472, PMID:28222186, PMID:34339468). Upon ligand recognition ALPK1 autophosphorylates and directly phosphorylates the adaptor TIFA at Thr9 (its primary site) and Thr177, with Thr9-FHA engagement driving TIFA oligomerization and liquid-liquid phase separation into TIFAsomes (PMID:28222186, PMID:36098982, PMID:37072480, PMID:38357697). These condensates recruit TRAF2/c-IAP1 and TRAF6, which generate K63- and M1-linked ubiquitin chains to activate TAK1/IKK and TBK1, amplifying inflammatory transcription (PMID:36098982, PMID:38357697). Kinase output is tuned by cofactors and context: copper binds ALPK1 directly and is required for kinase activity, enhancing ADP-heptose sensitivity during infection (PMID:38232278), while IFN-γ licenses the pathway in monocytes by inducing TIFA (PMID:39868044). Disease arises from gain-of-function kinase-domain mutations that expand ligand specificity to endogenous nucleotide sugars (UDP-mannose, ADP-ribose, GDP-mannose), causing constitutive NF-κB activation; the ROSAH syndrome variants T237M, Y254C and S277F and the spiradenoma driver V1092A all act through this mechanism of binding-pocket promiscuity (PMID:38060563, PMID:31101826, PMID:35868845, PMID:39626775). Beyond cytokine induction, ALPK1 signaling links bacterial sensing to additional cellular outcomes including replication stress and DNA double-strand breaks in infected gastric epithelium (PMID:33037203), apoptosis through c-IAP1 turnover (PMID:40357585), and microbial-metabolite-driven clonal hematopoiesis (PMID:40269158); ALPK1 agonism also drives CD8+ T cell-, DC- and macrophage-dependent antitumour immunity (PMID:41372408). ALPK1 additionally phosphorylates myosin IIA to regulate Golgi-derived TNF-α trafficking (PMID:27169898), and its NF-κB output contributes to chondrocyte and macrophage inflammation in osteoarthritis and TMJ pathology (PMID:35689396, PMID:36053817, PMID:38494837).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2017 High

    Established ALPK1 as the long-sought kinase that couples sensing of a bacterial heptose metabolite to TIFA-dependent NF-κB activation, defining a new innate immune axis.

    Evidence CRISPR/Cas9 knockout, recombinant protein, genome-wide RNAi screen, IF and immunoblot in epithelial cells responding to H. pylori βHBP and to Shigella/Salmonella/Neisseria HBP

    PMID:28222186 PMID:28877472

    Open questions at the time
    • Direct TIFA phosphorylation sites and stoichiometry not yet mapped
    • Structural basis of ligand recognition not resolved
    • Cofactor requirements unknown
  2. 2016 Medium

    Identified a kinase substrate beyond TIFA, linking ALPK1 to cytokine secretion machinery.

    Evidence Proteomics/Co-IP, knockdown and TNF-α secretion assays showing ALPK1 phosphorylates myosin IIA and complexes with calmodulin and F-actin in MSU-stimulated cells

    PMID:27169898

    Open questions at the time
    • Phosphosite on myosin IIA not defined
    • Relationship to the TIFA/NF-κB axis unclear
    • Single lab, no in vivo confirmation
  3. 2020 High

    Showed the ligand is the LPS intermediate β-ADP-heptose and that pathway activation has genotoxic consequences, expanding ALPK1 biology from cytokine induction to host-genome stress.

    Evidence Knockout/knockdown, R-loop IF, replication fork stalling assays and primary gastric organoids during H. pylori infection

    PMID:33037203

    Open questions at the time
    • Mechanism connecting NF-κB to R-loop accumulation incomplete
    • Long-term mutagenic consequences not quantified
  4. 2022 High

    Dissected the biochemical output of ALPK1 by mapping two TIFA phosphosites with opposite regulatory roles and the ubiquitin enzymology that amplifies signaling.

    Evidence In vitro kinase assays, phosphosite mutagenesis, ubiquitin chain analysis and Co-IP defining Thr9/Thr177 and TRAF2/TRAF6/c-IAP1 recruitment and TBK1 activation

    PMID:36098982

    Open questions at the time
    • In vivo relevance of Thr177 negative feedback untested
    • Spatial organization of ubiquitin assembly not addressed
  5. 2023 High

    Defined the molecular basis of ALPK1-driven disease as loss of ligand specificity, explaining constitutive autoinflammation in ROSAH and spiradenoma.

    Evidence Reporter and in vitro kinase assays with disease mutants (T237M, V1092A) and binding-site mutagenesis showing activation by endogenous nucleotide sugars; autophosphorylation confirmed

    PMID:37072480 PMID:38060563

    Open questions at the time
    • Identity of the physiologically relevant endogenous ligand in vivo unresolved
    • Tissue-specific phenotype variation not explained
  6. 2024 High

    Identified copper as a direct cofactor required for ALPK1 kinase activity, embedding nutritional immunity into pattern recognition.

    Evidence Direct copper-binding studies, in vitro kinase assays and zebrafish infection model showing copper enhances ADP-heptose sensitivity

    PMID:38232278

    Open questions at the time
    • Copper-binding site on ALPK1 not structurally mapped
    • Whether disease mutants alter copper dependence untested
  7. 2024 Medium

    Showed TIFAsome assembly is a phase-separation event nucleated by ALPK1 phosphorylation, providing a physical mechanism for signal amplification.

    Evidence Live-cell imaging of LLPS, domain mutants, ubiquitin chain analysis and chemical-probe inhibition demonstrating TRAF6 recruitment into condensates

    PMID:38357697

    Open questions at the time
    • Condensate composition not fully defined
    • In vivo demonstration of LLPS lacking
    • Single lab
  8. 2024 High

    Refined the structural rationale for variant-specific ligand promiscuity, showing pocket residue size rather than a specific hydrogen bond governs altered specificity.

    Evidence Crystal structure analysis combined with mutagenesis and in vitro kinase assays of the S277F ROSAH variant

    PMID:39626775

    Open questions at the time
    • No structure of ligand-bound mutant pocket
    • Endogenous ligand binding mode not visualized
  9. 2025 High

    Connected the ALPK1 axis to therapeutically relevant outcomes including antitumour immunity and microbial-metabolite-driven clonal hematopoiesis.

    Evidence Mouse tumour models with Alpk1 KO/T237M knockin, immune cell depletion and DC cross-presentation assays; pre-leukaemic cell transcriptomics, CH mouse models and serum ADP-heptose measurement

    PMID:40269158 PMID:41372408

    Open questions at the time
    • Translational dosing window for ALPK1 agonists undefined
    • Causal link between circulating ADP-heptose and human CH not proven
  10. 2025 Medium

    Extended ALPK1 function to cross-talk with other innate sensors and to non-canonical cell-death programs.

    Evidence Pathway reporter and immunoblot assays showing bidirectional ALPK1-STING cross-talk (preprint); Co-IP/pulldown/docking and KO mice linking ALPK1-HMGB1 interaction to microglial pyroptosis/ferroptosis after stroke

    PMID:39933362 PMID:40631099

    Open questions at the time
    • STING cross-talk is preprint and single lab
    • ALPK1-HMGB1 interaction interface not mapped
    • Whether kinase activity is required for HMGB1 effects unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ALPK1's non-immune and tissue-specific roles (ciliary localization, motor coordination, URAT1 regulation, testosterone modulation) mechanistically relate to its kinase/PRR activity remains unresolved.
  • No biochemical mechanism linking ALPK1 to ciliogenesis or motor control
  • Substrates outside TIFA/myosin IIA largely unmapped
  • Whether kinase activity underlies renal/endocrine phenotypes untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0140110 transcription regulator activity 3 GO:0140299 molecular sensor activity 3 GO:0140657 ATP-dependent activity 2
Localization
GO:0005829 cytosol 2 GO:0005815 microtubule organizing center 1 GO:0005929 cilium 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 3
Partners
BIRC2CALM1HMGB1MYH9TIFATRAF2TRAF6
Complex memberships
TIFAsome

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 ALPK1 is a kinase required for TIFA phosphorylation, TIFAsome formation, and NF-κB activation in response to the H. pylori T4SS-delivered metabolite D-glycero-β-D-manno-heptose 1,7-bisphosphate (βHBP). ALPK1 kinase activity is essential upstream of TIFA, as demonstrated by CRISPR/Cas9 knockout, recombinant protein experiments, immunoblotting, and immunofluorescence microscopy. CRISPR/Cas9 knockout, recombinant protein technology, immunofluorescence, immunoblotting, genome-wide RNAi screen, mass spectrometry Cell reports High 28877472
2017 ALPK1 is the critical kinase responsible for TIFA oligomerization and IL-8 expression in response to infection with Shigella flexneri, Salmonella typhimurium, and Neisseria meningitidis, acting upstream of TIFA/TRAF6/NF-κB. Threonine 9 and the forkhead-associated (FHA) domain of TIFA are required for TIFA oligomerization downstream of ALPK1. The trigger is the bacterial metabolite heptose-1,7-bisphosphate (HBP). Genome-wide RNAi screen, genetic knockdown, TIFA mutant constructs, NF-κB reporter assay, IL-8 ELISA PLoS pathogens High 28222186
2020 ALPK1/TIFA/NF-κB signaling pathway is activated by the bacterial LPS biosynthetic intermediate β-ADP-heptose (not just HBP), and this NF-κB-driven innate immune response causes R-loop-dependent replication stress and DNA double-strand breaks during S-phase in gastric epithelial cells infected by H. pylori. DNA damage depends on the ALPK1/TIFA pathway, co-transcriptional RNA/DNA hybrids, and H. pylori's RfaE enzyme and Cag pathogenicity island. Genetic knockout/knockdown, replication fork stalling assays, R-loop immunofluorescence, primary gastric organoids, immunoblotting Nature communications High 33037203
2016 ALPK1 phosphorylates myosin IIA in response to MSU crystals, and this phosphorylation regulates Golgi-derived TNF-α trafficking and secretion. ALPK1 forms a protein complex with myosin IIA (binding to ALPK1's N-terminal domain), calmodulin, and F-actin. Knockdown of ALPK1 or myosin IIA reduces MSU-induced TNF-α secretion. Bioinformatics, proteomics/Co-IP, cell knockdown models, TNF-α secretion assays, in vitro human assays Scientific reports Medium 27169898
2022 ADP-heptose stimulation of ALPK1 triggers formation of Lys63- and Met1-linked ubiquitin chains to activate TAK1 and canonical IKK complexes. E3 ligases TRAF6 and c-IAP1 redundantly generate Lys63-linked ubiquitin chains attached to TRAF6, TRAF2, and c-IAP1; c-IAP1 is recruited to TIFA via TRAF2. ALPK1 phosphorylates TIFA directly at both Thr9 and Thr177 in vitro; Thr177 phosphorylation (within the TRAF6-binding motif) restricts ADP-heptose signaling by preventing TRAF6 but not TRAF2 binding. ADP-heptose also activates TBK1 via TRAF2/TRAF6 in a TAK1-independent mechanism. In vitro kinase assay, ubiquitin chain analysis, mutagenesis of TIFA phosphorylation sites, Co-IP, immunoblotting The Biochemical journal High 36098982
2023 Disease-causing ALPK1 mutants (T237M for ROSAH, V1092A for spiradenoma) are activated not only by bacterial ADP-heptose but also by endogenous human nucleotide sugars (UDP-mannose, ADP-ribose, cyclic ADP-ribose; V1092A also by GDP-mannose), unlike wild-type ALPK1. This promiscuous activation can be suppressed by additional mutations in the ADP-heptose binding site, indicating the disease mechanism involves loss of ligand specificity in the binding pocket. NF-κB/AP-1 reporter assays in ALPK1 KO cells, site-directed mutagenesis of ADP-heptose binding site, in vitro kinase assays Proceedings of the National Academy of Sciences of the United States of America High 38060563
2023 ALPK1 phosphorylates TIFA at Thr9 (primary site), and also weakly at Thr2, Thr12, and Thr19 in vitro. ALPK1 itself undergoes autophosphorylation in response to ADP-heptose recognition during bacterial infection. Disease-associated ALPK1 mutants T237M and V1092A show enhanced ADP-heptose-induced kinase activity and constitutive TIFAsome assembly. Non-radioactive in vitro kinase assay (ATPγS/thiophosphorylation), infection models with S. flexneri and H. pylori, immunoblotting Scientific reports High 37072480
2024 Copper binds directly to ALPK1 and is essential for ALPK1 kinase activity. Host cells actively accumulate cytosolic copper during bacterial infection, and copper binding to ALPK1 enhances its sensitivity to ADP-heptose, promoting an enhanced innate immune response. ALPK1 kinase activity is required for copper-mediated host defense against both intracellular and extracellular bacteria. In vitro kinase assay, direct copper-binding studies, ALPK1-dependent pathway analysis, zebrafish in vivo model, cytokine measurement Proceedings of the National Academy of Sciences of the United States of America High 38232278
2024 TIFA undergoes liquid-liquid phase separation (LLPS) induced by ALPK1 upon ADP-heptose recognition. Phase separation of TIFA is driven by ALPK1 phosphorylation of pT9-FHA domain interaction and the intrinsically disordered region. TRAF6 is recruited into TIFA condensates and catalyzes K63-linked polyubiquitin chain synthesis within condensates, enabling downstream inflammatory signal amplification. Live-cell imaging of phase separation, phosphorylation assays, TIFA domain mutants, ubiquitin chain analysis, chemical probe (compound 22) inhibition Research (Washington, D.C.) Medium 38357697
2019 A recurrent missense mutation in the kinase domain of ALPK1 (found in spiradenomas and spiradenocarcinomas) activates the NF-κB pathway in reporter assays, acting as a gain-of-function oncogenic driver in sweat gland tumors. This ALPK1 mutation is mutually exclusive from CYLD mutation. Genomic sequencing of 75 tumor samples, NF-κB reporter assays with mutant ALPK1 constructs Nature communications Medium 31101826
2022 Gain-of-function ALPK1 mutations (T237M, Y254C) cause ROSAH syndrome through increased NF-κB signaling, STAT1 phosphorylation, and interferon gene expression. Knock-in mice with Alpk1 T237M mutation exhibit subclinical inflammation. Mutated ALPK1 constructs show increased immune activation in vitro. Immunoblotting of patient samples, in vitro mutant ALPK1 constructs, knock-in mice, transcriptomics, cytokine profiling Annals of the rheumatic diseases High 35868845
2019 The ALPK1 T237M heterozygous missense variant causes ROSAH syndrome. ALPK1 protein localizes to the basal body of the connecting cilium of photoreceptors, and to centrioles and spindle poles during metaphase and the base of the primary cilium. Fibroblasts from affected individuals demonstrate defective ciliogenesis. Exome/genome sequencing, immunofluorescence localization, ciliogenesis assays in patient fibroblasts Genetics in medicine Medium 30967659
2022 ALPK1 exacerbates condylar cartilage degradation in TMJOA by activating NF-κB signaling (upregulating MMP-13 and COX-2) and suppressing anabolism by inhibiting ERK1/2 (downregulating aggrecan) in chondrocytes. ALPK1 knockout mice showed attenuated cartilage and bone damage; intra-articular recombinant ALPK1 aggravated pathology. ALPK1 knockout mice, intra-articular administration of recombinant ALPK1, ex vivo chondrocyte assays, NF-κB and ERK1/2 pathway inhibitors, MIA-induced TMJOA model Journal of dental research Medium 35689396
2022 ALPK1 accelerates osteoarthritis pathogenesis by enhancing NLRP3 inflammasome production in chondrocytes, driving IL-1β-mediated inflammation. NLRP3 operates downstream of NF-κB in ALPK1-activated chondrocytes. ALPK1 knockout reversed OA pathogenesis in DMM and CIOA mouse models. ALPK1 knockout mice, DMM and CIOA mouse OA models, intraarticular rhALPK1 administration, NF-κB inhibitor, NLRP3 inhibitor, in vitro chondrocyte assays Journal of bone and mineral research Medium 36053817
2025 ADP-heptose binds ALPK1 and triggers transcriptional reprogramming and NF-κB activation in pre-leukaemic haematopoietic cells, endowing them with a competitive proliferative advantage that promotes clonal haematopoiesis expansion. ADP-heptose is found in the circulation of older individuals, linking microbial metabolite dissemination to pre-leukaemic cell expansion via the ALPK1 axis. In vitro ADP-heptose treatment of pre-leukaemic cells, NF-κB reporter assays, transcriptomics, mouse models of clonal haematopoiesis, serum ADP-heptose measurement Nature High 40269158
2025 ALPK1 activation enhances STING pathway outputs including canonical NF-κB/IRF3 signaling, STING proton channel-dependent LC3B lipidation, and NLRP3 inflammasome activation. Conversely, STING activation increases ALPK1 protein expression and triggers TIFA-Thr9 phosphorylation, establishing bidirectional cross-talk between ALPK1 and STING pathways. ALPK1 signaling also activates eIF2α (integrated stress response). Pathway reporter assays, immunoblotting for phosphorylated TIFA-T9, STING pathway markers, LC3B lipidation assay, NLRP3 inflammasome activation assays bioRxivpreprint Medium 40631099
2025 ALPK1 is required for H. pylori-induced apoptosis in gastric epithelial cells. Absence of ALPK1 leads to accumulation of cIAP1 upon H. pylori infection, raising the apoptosis threshold. Ablation of cIAP1 with a SMAC-mimetic restores apoptosis levels in ALPK1-deficient cells, placing ALPK1-dependent cIAP1 degradation upstream of the apoptotic threshold. ALPK1 knockout/ablation, SMAC-mimetic treatment, immunoblotting for cIAP1, apoptosis assays FASEB journal Medium 40357585
2024 IFN-γ is required to license the ALPK1/TIFA pathway in human monocytes (but not B cells). IFN-γ induces TIFA upregulation in monocytes, and TIFA induction alone is sufficient to recapitulate the licensing effect. JAK inhibitors block the IFN-γ licensing effect on ALPK1 function in monocytes. Human mononuclear cell assays, IFN-γ treatment, TIFA overexpression, JAK inhibitor treatment, NF-κB signaling readouts iScience Medium 39868044
2024 ALPK1 Ser277Phe (novel ROSAH variant) is activated by bacterial ADP-heptose and additionally by human metabolites UDP-mannose and ADP-ribose (more strongly than T237M) and by GDP-mannose (unlike T237M). Structural analysis shows Ser277 and Tyr254 sidechains interact in the crystal structure of ALPK1, but mutational analysis established that loss of this hydrogen bond is not what alters ADP-heptose binding pocket specificity — rather it is the replacement by large hydrophobic (Phe) or small (Cys) residues that alters specificity. NF-κB/AP-1 reporter assays, in vitro kinase assays, site-directed mutagenesis, crystal structure analysis Open biology High 39626775
2021 Campylobacter jejuni releases ADP-heptose and/or related heptose phosphates (identified by deletion of hldE heptose-biosynthesis gene) that activate ALPK1-dependent NF-κB signaling, inducing CXCL8 and other inflammatory genes in intestinal epithelial cells. This pathway is independent of Toll-like Receptor and Nod-like Receptor signaling and does not require a T3SS or T4SS. ALPK1 genetic knockout in intestinal cells, hldE deletion mutant bacteria, NF-κB reporter assays, cytokine measurement, chemical characterization of released factor PLoS pathogens High 34339468
2017 ALPK1 overexpression decreases URAT1 (SLC22A12) protein expression in vivo in transgenic mice and in vitro in kidney cells. MSU crystals inhibit URAT1 expression through ALPK1 upregulation. Endogenous ALPK1 protein is detected in renal proximal tubule cells. ALPK1 transgenic mice (Western blot for URAT1), ALPK1 siRNA knockdown in HK-2 cells, immunohistochemistry Rheumatology (Oxford, England) Medium 28039413
2019 ALPK1 regulates streptozotocin-induced nephropathy through upregulation of CCL2/MCP-1 and CCL5/RANTES chemokines. Knockdown of ALPK1 reduced CCL2 and CCL5 mRNA levels; overexpression increased them in kidney cells. High glucose increases ALPK1 expression and activates NF-κB in kidney cells. ALPK1 transgenic mice (STZ model), cytokine array, ALPK1 siRNA knockdown, ALPK1 overexpression, qPCR, immunohistochemistry Journal of cellular and molecular medicine Medium 31557402
2015 ALPK1 modulates testosterone-mediated regulation of proinflammatory cytokines. Decreasing endogenous ALPK1 enhanced testosterone levels and testosterone-regulated gene transcripts in Leydig cells. Increased ALPK1 attenuated testosterone's anti-inflammatory effects in THP1 cells. ALPK1 overexpression increased TNF-α and TGF-β1 release, while testosterone inhibited ALPK1 in primary kidney cells. ALPK1 transgenic mice, siRNA knockdown in TM3 Leydig cells, ALPK1 OE in THP1 cells, ELISA for cytokines, RT-qPCR The Journal of steroid biochemistry and molecular biology Low 26275947
2025 ALPK1 agonism (ADP-heptose or synthetic analogue UDSP-Hep) induces antitumour immunity in an Alpk1-dependent manner. The antitumour effect requires CD8+ T cells, dendritic cells, and macrophages, and involves CXCL10 and CCL2. ALPK1 agonists activate DCs for cross-presentation, promoting tumour-specific T cell expansion in tumour-draining lymph nodes. ALPK1 also stimulates tumour-cell antigen presentation. Mouse tumour models with Alpk1 KO and gain-of-function T237M knockin, antibody blockade (anti-CXCL10, anti-CCL2), immune cell depletion, DC cross-presentation assays Nature High 41372408
2011 ALPK1 plays a role in motor coordination regulation in mice. PiggyBac transposon insertion into Alpk1 intron 1 disrupts Alpk1 transcript expression and causes severe motor coordination deficits (dowel, hanging wire, rotarod, footprint tests). Cerebellar architecture and Purkinje cell morphology and electrophysiology appear normal. Motor deficits are rescued by transgenic full-length Alpk1 expression. PiggyBac transposon insertional mutagenesis, behavioral analysis (multiple motor tests), transgenic rescue, cerebellar histology and electrophysiology BMC neuroscience Medium 21208416
2022 Akkermansia muciniphila activates NF-κB in intestinal epithelial cells via release of a metabolite with characteristics of ADP-heptose that enters epithelial cells and activates NF-κB through ALPK1, TIFA, and TRAF6. This leads to upregulation of MUC2, BIRC3, and TNFAIP3 genes in a TIFA-dependent manner. Chemical inhibitors, gene-editing (ALPK1/TIFA/TRAF6 KO), NF-κB reporter assays, qPCR for target genes, metabolite characterization Gut microbes Medium 36036242
2022 ALPK1 promotes TMJ synovitis by promoting nuclear PKM2-mediated M1 macrophage polarization. LMW-HA promotes ALPK1 expression and M1 macrophage genes; recombinant ALPK1 promotes nuclear PKM2 translocation. ALPK1 KO mice showed limited macrophage infiltration in CFA-induced TMJ synovitis. HMW-HA inhibits ALPK1 expression and M1 polarization. ALPK1 KO mice, recombinant ALPK1 treatment, LMW-HA/HMW-HA treatment, immunofluorescence for nuclear PKM2, flow cytometry Journal of cellular and molecular medicine Medium 38494837
2023 Fusobacterium nucleatum releases ADP-heptose that activates the ALPK1/TIFA/TRAF6 NF-κB pathway in intestinal epithelial cells, increasing IL-8 and anti-apoptotic genes BIRC3 and TNFAIP3, and promoting survival of CRC cells and reduced 5-fluorouracil chemosensitivity. ALPK1/TIFA/TRAF6 KO cell lines, conditioned medium characterization, hldE bacterial deletion mutant, NF-κB reporter, cytokine ELISA, apoptosis assays Gut microbes High 38126163
2023 ALPK1 expressed in IB4-positive neurons of trigeminal ganglia promotes TMJ pain. ALPK1 is upregulated in trigeminal ganglion neurons following intra-TMJ MIA injection; ALPK1-/- mice show attenuated pain behavior and decreased IB4+ neuron sensitization. Recombinant ALPK1 enhances calcium responses in Dil+ neurons. ALPK1 KO mice, behavioral pain assays, immunofluorescence double staining, calcium imaging in neurons, recombinant protein treatment Molecular neurobiology Medium 37442857
2022 ALPK1, identified as a novel pattern recognition receptor, mediates Fusobacterium nucleatum-induced ICAM1 upregulation via NF-κB pathway activation, enhancing CRC cell adhesion to endothelial cells, extravasation, and metastasis. ALPK1 knockdown in CRC cells, NF-κB reporter assays, adhesion assays, in vivo extravasation/metastasis models, immunohistochemistry Gut microbes Medium 35220887
2025 ALPK1 promotes microglial pyroptosis and ferroptosis following ischemic stroke via interaction with HMGB1. Co-immunoprecipitation, pulldown assay, and molecular docking revealed a direct physical interaction between HMGB1 and ALPK1. ALPK1 deficiency mitigated HMGB1-induced pyroptosis and ferroptosis by inhibiting NLRP3/Caspase-1/GSDMD and JAK2/STAT3 signaling pathways. Co-immunoprecipitation, pulldown assay, molecular docking, ALPK1 KO in tMCAO mice, co-immunofluorescence, pyroptosis/ferroptosis assays International immunopharmacology Medium 39933362
2021 Alpk1 activation by ADP-heptose sensitizes pancreatic beta cells to cytokine-induced apoptosis by potentiating TNF-α and Fas expression via enhanced TIFA/TAK1/NF-κB signaling. Alpk1 activation alone was insufficient to induce beta cell apoptosis but significantly exacerbated cytokine-induced apoptosis. ADP-heptose treatment of MIN6 cells, Alpk1 activation/inhibition, TIFA/TAK1/NF-κB pathway analysis, apoptosis assays, cytokine measurement Frontiers in immunology Medium 34621265
2026 SETDB2 suppresses ALPK1 expression in macrophages via increased H3K9me3 enrichment at the ALPK1 locus, and ALPK1 overexpression reverses the beneficial effects of SETDB2 on chondrocyte behavior, establishing SETDB2 as an epigenetic repressor of ALPK1 in macrophage polarization. ChIP-qPCR for H3K9me3 at ALPK1 locus, SETDB2 KD and OE, ALPK1 OE rescue experiments, flow cytometry for macrophage polarization FASEB journal Medium 41482828

Source papers

Stage 0 corpus · 60 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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 175 35220887
2017 ALPK1- and TIFA-Dependent Innate Immune Response Triggered by the Helicobacter pylori Type IV Secretion System. Cell reports 148 28877472
2017 ALPK1 controls TIFA/TRAF6-dependent innate immunity against heptose-1,7-bisphosphate of gram-negative bacteria. PLoS pathogens 106 28222186
2020 The ALPK1/TIFA/NF-κB axis links a bacterial carcinogen to R-loop-induced replication stress. Nature communications 91 33037203
2022 Akkermansia muciniphila upregulates genes involved in maintaining the intestinal barrier function via ADP-heptose-dependent activation of the ALPK1/TIFA pathway. Gut microbes 68 36036242
2019 ALPK1 hotspot mutation as a driver of human spiradenoma and spiradenocarcinoma. Nature communications 67 31101826
2022 Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome. Annals of the rheumatic diseases 59 35868845
2019 ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder. Genetics in medicine : official journal of the American College of Medical Genetics 54 30967659
2011 Motor coordination deficits in Alpk1 mutant mice with the inserted piggyBac transposon. BMC neuroscience 54 21208416
2024 Copper regulates the host innate immune response against bacterial infection via activation of ALPK1 kinase. Proceedings of the National Academy of Sciences of the United States of America 53 38232278
2023 Fusobacterium nucleatum promotes inflammatory and anti-apoptotic responses in colorectal cancer cells via ADP-heptose release and ALPK1/TIFA axis activation. Gut microbes 53 38126163
2013 Identification of chromosome 3q28 and ALPK1 as susceptibility loci for chronic kidney disease in Japanese individuals by a genome-wide association study. Journal of medical genetics 50 23539754
2013 ALPK1 genetic regulation and risk in relation to gout. International journal of epidemiology 39 23569188
2020 ADP-heptose: a bacterial PAMP detected by the host sensor ALPK1. Cellular and molecular life sciences : CMLS 33 32591860
2025 Microbial metabolite drives ageing-related clonal haematopoiesis via ALPK1. Nature 31 40269158
2022 ALPK1 Aggravates TMJOA Cartilage Degradation via NF-κB and ERK1/2 Signaling. Journal of dental research 30 35689396
2021 The ALPK1 pathway drives the inflammatory response to Campylobacter jejuni in human intestinal epithelial cells. PLoS pathogens 29 34339468
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 : EJHG 26 31053777
2025 Fusobacterium nucleatum upregulates the immune inhibitory receptor PD-L1 in colorectal cancer cells via the activation of ALPK1. Gut microbes 24 39881579
2016 ALPK1 phosphorylates myosin IIA modulating TNF-α trafficking in gout flares. Scientific reports 24 27169898
2020 Juvenile Onset Splenomegaly and Oculopathy Due to Germline Mutation in ALPK1. Journal of clinical immunology 21 31939038
2016 ERN1 and ALPK1 inhibit differentiation of bi-potential tumor-initiating cells in human breast cancer. Oncotarget 21 27829216
2019 ALPK1 regulates streptozotocin-induced nephropathy through CCL2 and CCL5 expressions. Journal of cellular and molecular medicine 20 31557402
2015 ALPK1 affects testosterone mediated regulation of proinflammatory cytokines production. The Journal of steroid biochemistry and molecular biology 20 26275947
2019 Role of NOD1 and ALPK1/TIFA Signalling in Innate Immunity Against Helicobacter pylori Infection. Current topics in microbiology and immunology 19 31123889
2022 Co-ordinated control of the ADP-heptose/ALPK1 signalling network by the E3 ligases TRAF6, TRAF2/c-IAP1 and LUBAC. The Biochemical journal 18 36098982
2022 Alpha-kinase 1 (ALPK1) agonist DF-006 demonstrates potent efficacy in mouse and primary human hepatocyte (PHH) models of hepatitis B. Hepatology (Baltimore, Md.) 17 35699669
2022 ALPK1 Accelerates the Pathogenesis of Osteoarthritis by Activating NLRP3 Signaling. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 17 36053817
2025 ALPK1 signaling pathway activation by HMGB1 drives microglial pyroptosis and ferroptosis and brain injury after acute ischemic stroke. International immunopharmacology 16 39933362
2023 ALPK1 mutants causing ROSAH syndrome or Spiradenoma are activated by human nucleotide sugars. Proceedings of the National Academy of Sciences of the United States of America 16 38060563
2021 Alpk1 Sensitizes Pancreatic Beta Cells to Cytokine-Induced Apoptosis via Upregulating TNF-α Signaling Pathway. Frontiers in immunology 16 34621265
2017 URAT1 inhibition by ALPK1 is associated with uric acid homeostasis. Rheumatology (Oxford, England) 16 28039413
2016 Down-regulated and Commonly mutated ALPK1 in Lung and Colorectal Cancers. Scientific reports 16 27283888
2024 The relationship of ALPK1, hyaluronic acid and M1 macrophage polarization in the temporomandibular joint synovitis. Journal of cellular and molecular medicine 14 38494837
2018 ALPK1 Expression Is Associated with Lymph Node Metastasis and Tumor Growth in Oral Squamous Cell Carcinoma Patients. The American journal of pathology 14 30315765
2024 Discovery and functional analysis of a novel ALPK1 variant in ROSAH syndrome. Open biology 12 39626775
2024 ADP-Hep-Induced Liquid Phase Condensation of TIFA-TRAF6 Activates ALPK1/TIFA-Dependent Innate Immune Responses. Research (Washington, D.C.) 8 38357697
2020 CD14 and ALPK1 Affect Expression of Tight Junction Components and Proinflammatory Mediators upon Bacterial Stimulation in a Colonic 3D Organoid Model. Stem cells international 8 32076438
2014 Common variant of ALPK1 is not associated with gout: a replication study. Human cell 8 25326865
2023 In vitro kinase assay reveals ADP-heptose-dependent ALPK1 autophosphorylation and altered kinase activity of disease-associated ALPK1 mutants. Scientific reports 7 37072480
2025 Agonists for cytosolic bacterial receptor ALPK1 induce antitumour immunity. Nature 6 41372408
2023 ALPK1 Expressed in IB4-Positive Neurons of Mice Trigeminal Ganglions Promotes MIA-Induced TMJ pain. Molecular neurobiology 5 37442857
2024 IFN-γ licenses normal and pathogenic ALPK1/TIFA pathway in human monocytes. iScience 4 39868044
2025 Ocular Manifestations of ROSAH Syndrome Caused by Different Mutations of the ALPK1 Gene. American journal of ophthalmology 3 41046116
2025 Impact of glioma metabolism-related gene ALPK1 on tumor immune heterogeneity and the regulation of the TGF-β pathway. Frontiers in immunology 2 39845963
2024 Ischemic stroke susceptibility associated with ALPK1 single nucleotide polymorphisms by inhibiting URAT1 in uric acid hemostasis. Gene 2 39437898
2026 SETDB2 Alleviates Knee Osteoarthritis Progression by Promoting M2-Like Macrophage Polarization via Targeting ALPK1. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 1 41482828
2024 Quantitative Measurement of the Kinase Activity of Wildtype ALPK1 and Disease-Causing ALPK1 Mutants Using Cell-Free Radiometric Phosphorylation Assays. Bio-protocol 1 39600973
2024 Measurement of the Activity of Wildtype and Disease-Causing ALPK1 Mutants in Transfected Cells With a 96-Well Format NF-κB/AP-1 Reporter Assay. Bio-protocol 1 39600975
2023 The Role of ALPK1 in Inhibiting Hepatitis B Virus Replication Facilitates the Identification of ALPK1 P660L Variant for Predicting Response to Pegylated Interferon α Therapy. The Journal of infectious diseases 1 36932045
2018 ALPK1: a pattern recognition receptor for bacterial ADP-heptose. Precision clinical medicine 1 35693201
2026 Determinate the effects of Arabic gum and Lactobacillus acidophilus on the gut microbiota ALPK1/NFKB/NLRP6 and NLRP2 signaling pathway and virulence gene profile in rats with Campylobacter jejuni exosome application. Archives of microbiology 0 41711913
2026 ALPK1 agonists ignite innate immunity in anticancer therapy. Trends in cancer 0 41760443
2026 ADP-heptose/ALPK1 signaling pathway: Function, regulation, and involvement in diseases. Cellular signalling 0 41833772
2026 ALPK1 promotes cardiomyocyte hypertrophy by activating NF-κB/NLRP3 inflammasome-mediated pyroptosis. Experimental cell research 0 42061549
2025 ALPK1-Dependent cIAP1 Degradation Regulates Helicobacter pylori-Induced Apoptosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 40357585
2025 The importance of ALPK1 kinase functionality as a potential biomarker for inflammatory diseases. Molecular biology reports 0 40493324
2025 Crosstalk Between ALPK1 and STING: A Synergistic Axis in Innate Immune Activation and Human Inflammatory Disease. bioRxiv : the preprint server for biology 0 40631099
2025 Investigating the role of the ALPK1 signaling pathway in the pathogenesis of diabetic retinopathy. Scientific reports 0 41006430
2025 Immune function analysis in a pediatric patient with a de novo ALPK1 gene mutation. Frontiers in immunology 0 41235249

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