Alpk1, or alpha-kinase 1, is an atypical protein kinase and a pattern recognition receptor. It is activated by the bacterial nucleotide sugar ADP-heptose and phosphorylates TIFA to activate the NF-κB signaling pathway, which is crucial for combating microbial infection [1]. It also has a role in innate immunity and is involved in various biological processes related to inflammation [2,3,4]. Genetic models, such as mouse models, are valuable for studying its function.

In KO mouse models, Alpk1 knockout reversed the exacerbation of osteoarthritis (OA) pathogenesis in two different mouse OA models (destabilized medial meniscus and collagenase-induced OA), suggesting that Alpk1 accelerates OA by activating NLRP3 signaling [5]. In temporomandibular joint osteoarthritis (TMJOA) mouse models, Alpk1 knockout mice showed attenuated damage of cartilage and subchondral bone, as well as synovitis, indicating that Alpk1 exacerbates TMJOA cartilage degradation through the NF-κB and ERK1/2 signaling pathways [6].

In conclusion, Alpk1 is essential in the activation of innate immune responses via the NF-κB pathway. Studies using KO mouse models have revealed its role in accelerating the pathogenesis of osteoarthritis-related diseases. Understanding Alpk1's functions can provide potential therapeutic targets for treating these inflammatory-related joint diseases.

References:

1. Snelling, Tom, Saalfrank, Anton, Wood, Nicola T, Cohen, Philip. 2023. ALPK1 mutants causing ROSAH syndrome or Spiradenoma are activated by human nucleotide sugars. In Proceedings of the National Academy of Sciences of the United States of America, 120, e2313148120. doi:10.1073/pnas.2313148120. https://pubmed.ncbi.nlm.nih.gov/38060563/

2. Xu, Cong, Fan, Jieqing, Liu, Danyang, Lichenstein, Henri, Xu, Tian. 2022. Alpha-kinase 1 (ALPK1) agonist DF-006 demonstrates potent efficacy in mouse and primary human hepatocyte (PHH) models of hepatitis B. In Hepatology (Baltimore, Md.), 77, 275-289. doi:10.1002/hep.32614. https://pubmed.ncbi.nlm.nih.gov/35699669/

3. Lu, Jing, Liu, Xue, Li, Xinghua, Sun, Hongzhe, Yang, Xinming. 2024. Copper regulates the host innate immune response against bacterial infection via activation of ALPK1 kinase. In Proceedings of the National Academy of Sciences of the United States of America, 121, e2311630121. doi:10.1073/pnas.2311630121. https://pubmed.ncbi.nlm.nih.gov/38232278/

4. Martin-Gallausiaux, Camille, Salesse, Laurène, Garcia-Weber, Diego, Arrieumerlou, Cécile, Lapaque, Nicolas. 2023. Fusobacterium nucleatum promotes inflammatory and anti-apoptotic responses in colorectal cancer cells via ADP-heptose release and ALPK1/TIFA axis activation. In Gut microbes, 16, 2295384. doi:10.1080/19490976.2023.2295384. https://pubmed.ncbi.nlm.nih.gov/38126163/

5. Liu, Xin, Zhao, Jie, Jiang, Henghua, Ke, Jin, Long, Xing. 2022. ALPK1 Accelerates the Pathogenesis of Osteoarthritis by Activating NLRP3 Signaling. In Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 37, 1973-1985. doi:10.1002/jbmr.4669. https://pubmed.ncbi.nlm.nih.gov/36053817/

6. Liu, X, Zhao, J, Jiang, H, Ke, J, Long, X. 2022. ALPK1 Aggravates TMJOA Cartilage Degradation via NF-κB and ERK1/2 Signaling. In Journal of dental research, 101, 1499-1509. doi:10.1177/00220345221100179. https://pubmed.ncbi.nlm.nih.gov/35689396/