Alpk1-flox Mouse

Alpk1, an atypical protein kinase, is a pattern recognition receptor (PRR) that activates the NF-κB pathway, playing a crucial role in innate immunity [3,4,5,6]. It is activated by the bacterial nucleotide sugar ADP-heptose and phosphorylates TIFA to initiate a signaling pathway against microbial infection [2].

In ROSAH syndrome, gain-of-function mutations in ALPK1 lead to an NF-κB-mediated autoinflammatory disease, with patients showing various inflammatory features [1]. Alpk1 knock-in mice with the T237M mutation exhibit subclinical inflammation, demonstrating its role in this autoinflammatory disease [1].

In colorectal cancer, Fusobacterium nucleatum promotes cancer cell adhesion to endothelial cells and metastasis by inducing the ALPK1/NF-κB/ICAM1 axis. High ALPK1 expression in patients is associated with shorter survival times [3].

In hepatitis B models, the ALPK1 agonist DF-006 shows anti-HBV efficacy, reducing viral markers and upregulating NF-κB-targeted genes involved in innate immunity [4].

In osteoarthritis (OA) mouse models, elevation of ALPK1 in degraded cartilage is observed. Intra-articular administration of recombinant human ALPK1 exacerbates OA, while ALPK1 knockout reverses this process, indicating ALPK1 accelerates OA pathogenesis by activating NLRP3 signaling [7].

In temporomandibular joint osteoarthritis (TMJOA) mouse models, ALPK1 knockout mice have attenuated cartilage and subchondral bone damage, as well as synovitis, compared to wild-type mice, suggesting ALPK1 exacerbates TMJOA cartilage degradation through the NF-κB and ERK1/2 signaling pathways [8].

In streptozotocin-induced nephropathy, high glucose increases ALPK1 levels, and elevated ALPK1 enhances renal CCL2 and CCL5 expressions, suggesting ALPK1 is a mediator in diabetic nephropathies induction [9].

In conclusion, Alpk1 is a key regulator in the NF-κB-related immune signaling pathway. Its gain-of-function mutations cause autoinflammatory diseases like ROSAH syndrome. In various disease models, Alpk1 has been shown to play significant roles in promoting disease progression, such as in cancer metastasis, viral infection, and degenerative joint diseases. Gene knockout and knock-in mouse models have been instrumental in revealing these functions, providing insights into the underlying disease mechanisms and potential therapeutic targets.