THE ALPK1 RECEPTOR RECOGNIZES BACTERIAL SIGNALS INSIDE THE CELL

Martinotti S. The ALPK1 receptor recognizes bacterial signals inside the cell. International Journal of Infection. 2026;10(1):14-15.

S. Martinotti^*

University “Gabriele d’Annunzio” of Chieti-Pescara, Chieti, Italy.

*Correspondence to:
Stefano Martinotti,
University “Gabriele d’Annunzio” of Chieti-Pescara,
Chieti, Italy.
e-mail: stefano.martinotti@unich.it

Received: 11 March, 2026 Accepted: 20 April, 2026

ISSN 3103-6678 [online] Copyright 2026 © by Biolife-publisher This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: all authors report no conflicts of interest relevant to this article.

KEYWORDS: ALPK1, kinase, receptor, bacteria, cell

INTRODUCTION

Alpha kinase 1 (ALPK1) is a protein from the alpha-kinase family that, unlike many other immune receptors found on membranes or in extracellular compartments, acts within the cytosol (1). The cytoplasmic matrix is a gelatinous fluid component of the cytoplasm in which all cell organelles, excluding the nucleus and membranous organelles, are immersed. It represents approximately 52% of the cell volume and serves as the site of fundamental metabolic reactions. ALPK1 does not directly recognize whole bacteria but detects ADP-L-glycero-D-mannoheptose (ADP-heptose), a specific molecule produced by many Gram-negative bacteria (2).

DISCUSSION

In a recent interesting article, Tian et al. examined the anti-tumor function of the bacterial ADP-heptose receptor ALPK1 and found that treatment of mice with ADP-Hep induced the production of several pro-inflammatory factors and stimulated ALPK1-dependent antitumor immunity. The article concludes that ALPK1 agonists activate dendritic cells for cross-presentation, promoting the expansion of tumor-specific T cells in tumor-draining lymph nodes. The study clarifies the anti-tumor effect of ALPK1 and suggests the potential role of ALPK1 agonists in cancer immunotherapy (3).

ALPK1 detects molecules derived from Gram-negative bacteria, making it a cytosolic pattern recognition receptor (PRR) distinct from Toll-like receptors (TLRs). When heparin binding protein (HBP) enters the cytosol of the infected cell, ALPK1 binds to HBP. ADP-heptose is an intermediate molecule in the biosynthesis of lipopolysaccharide (LPS), a key component of the bacterial cell wall. When ADP-heptose enters the host cell, ALPK1 is activated and phosphorylates the TRAF interacting protein with forkhead associated domain (TIFA) protein. This then forms a complex called the TIFAsome, which activates the NF-κB pathway (4).

The TIFAsome is a multiprotein complex and intracellular sensor of bacterial metabolites that forms around the TIFA and is involved in the innate immune response, particularly against bacteria. The TIFAsome activates the NF-κB pathway through bacterial molecular recognition (LPS biosynthesis). LPS enters the host cell and triggers an alarm. At this point, the TIFAsome is phosphorylated by HBP on the specific threonine Thr9 and changes conformation (5).

HBP is secreted by neutrophils and is a promising diagnostic biomarker that predicts organ dysfunction following sepsis. It has high sensitivity and specificity and can accurately distinguish patients with sepsis from those without. This biomarker is valid and reproducible even in different contexts and is reliable for rapidly diagnosing the progression to severe sepsis with organ dysfunction. HBP is produced by neutrophils (where it resides independently of the immune response) and is the first to respond against pathogenic microorganisms. HBP resides in neutrophil vesicles and significantly mediates vascular permeability and inflammation after a sepsis event. Clinically, it has been noted that patients with sepsis can express elevated plasma HBP levels even several hours before organ dysfunction and hypotension develop (6).

TIFA is phosphorylated via its FHA domain and forms the TIFAsome complex, which recruits the adaptor protein TRAF6. The TIFAsome is not a single protein, and it does not self-oligomerize, whereas TIFA does. Binding of an E3 ubiquitin ligase triggers immune signaling. Activated TRAF6 promotes polyubiquitination, which activates the TAK1 complex, which in turn activates the IKK complex, leading to the activation of NF-κB. Activated NF-κB translocates to the nucleus and activates pro-inflammatory cytokine genes. Without ALPK1, TIFA is not phosphorylated, the TIFAsome does not form, and NF-κB is not activated in response to HBP.

CONCLUSION

ALPK1 acts against intracellular bacteria by sensing bacterial metabolites and activates NF-κB, promoting an antibacterial inflammatory response, particularly against Gram-negative pathogens. ALPK1 is an early cytosolic sensor of bacterial invasion and contributes to the maintenance of immune defenses. It is implicated in inflammation, and persistent activation or deregulation of the ALPK1–TIFA pathway may contribute to local and systemic inflammatory states.

Conflict of interest

The author declares that they have no conflict of interest.

REFERENCES

1. Zhou P, She Y, Dong N, et al. Alpha-kinase 1 is a cytosolic innate immune receptor for bacterial ADP-heptose. Nature. 2018;561(7721):122-126. doi:https://doi.org/10.1038/s41586-018-0433-3
2. Cui X, Li Y, Yuan S, et al. Alpha‐kinase1 promotes tubular injury and interstitial inflammation in diabetic nephropathy by canonical pyroptosis pathway. Biological Research. 2023;56(1). doi:https://doi.org/10.1186/s40659-023-00416-7
3. Tian X, Liu J, Li Y, et al. Agonists for cytosolic bacterial receptor ALPK1 induce antitumour immunity. Nature. 2025;650(8100):242-250. doi:https://doi.org/10.1038/s41586-025-09828-9
4. Zimmermann S, Lennart Pfannkuch, Al-Zeer MA, et al. ALPK1- and TIFA-Dependent Innate Immune Response Triggered by the Helicobacter pylori Type IV Secretion System. Cell Reports. 2017;20(10):2384-2395. doi:https://doi.org/10.1016/j.celrep.2017.08.039
5. Lynn S, Kanyi D, Hamel M, et al. Heparin Decreases in Tumor Necrosis Factor α (TNFα)-induced Endothelial Stress Responses Require Transmembrane Protein 184A and Induction of Dual Specificity Phosphatase 1. Journal of Biological Chemistry. 2016;291(10):5342-5354. doi:https://doi.org/10.1074/jbc.m115.681288
6. Chaudhuri D, Nei AM, Bram Rochwerg, et al. 2024 Focused Update: Guidelines on Use of Corticosteroids in Sepsis, Acute Respiratory Distress Syndrome, and Community-Acquired Pneumonia. Critical Care Medicine. 2024;52(5). doi:https://doi.org/10.1097/ccm.0000000000006172