Ikbkb, also known as IKKβ (IkappaB kinase beta) or IKK2, is a key molecule in the signaling pathway to the transcription factor NF-κB. Its kinase activity phosphorylates IkappaB molecules, leading to their ubiquitination and proteasomal degradation, and subsequent release and activation of NF-κB. NF-κB has diverse functions in regulating the immune system, cellular differentiation, survival, and proliferation, making Ikbkb crucial in biological processes [8].

In Huntington's disease, Ikbkb can phosphorylate serine 13 of huntingtin via a non-canonical interferon regulatory factor3-mediated IKK pathway, reducing mutant huntingtin aggregation [1]. A heterozygous gain-of-function (GOF) Ikbkb variant in a male infant was associated with autoimmunity and autoinflammation [2]. In spinal nerve ligation (SNL) rats, delivering Ikbkb small interfering RNA (siRNA)-encapsulated poly (lactic-co-glycolic acid) (PLGA) nanoparticles reduced neuropathic pain by inhibiting microglial activation [3]. In hepatocellular carcinoma (HCC), IKKβ phosphorylated and stabilized USP30, promoting lipogenesis and tumorigenesis [4]. In clear cell renal cell carcinoma (ccRCC), upregulated Ikbkb protein expression was related to higher nuclear grade tumors and shorter patient survival [5]. In gliomagenesis, α-ketoglutarate produced by GDH1 binds to and activates IKKβ, promoting glucose uptake and tumor cell survival [6]. In osteoarthritis, decreased miR-214-3p activated the NF-κB pathway by targeting Ikbkb, aggravating disease progression [7]. A gain-of-function Ikbkb mutation in humans caused combined immune deficiency, and a mouse model with the orthologous codon change showed similar cellular and biochemical phenotypes [9].

In summary, Ikbkb is essential in the NF-κB signaling pathway, influencing multiple biological processes and disease conditions. Studies using gene-based models, such as the mouse model with a gain-of-function Ikbkb mutation, have revealed its role in diseases like Huntington's disease, autoimmunity, neuropathic pain, cancer, and osteoarthritis, providing insights into disease mechanisms and potential therapeutic targets.

References:

1. Cariulo, Cristina, Martufi, Paola, Verani, Margherita, Petricca, Lara, Caricasole, Andrea. 2023. IKBKB reduces huntingtin aggregation by phosphorylating serine 13 via a non-canonical IKK pathway. In Life science alliance, 6, . doi:10.26508/lsa.202302006. https://pubmed.ncbi.nlm.nih.gov/37553253/

2. Sacco, Keith, Kuehn, Hye Sun, Kawai, Tomoki, Rosenzweig, Sergio D, Keller, Michael D. 2022. A Heterozygous Gain-of-Function Variant in IKBKB Associated with Autoimmunity and Autoinflammation. In Journal of clinical immunology, 43, 512-520. doi:10.1007/s10875-022-01395-2. https://pubmed.ncbi.nlm.nih.gov/36378426/

3. Lee, Seounghun, Shin, Hyo-Jung, Noh, Chan, Lee, Won-Hyung, Kim, Yoon-Hee. 2021. IKBKB siRNA-Encapsulated Poly (Lactic-co-Glycolic Acid) Nanoparticles Diminish Neuropathic Pain by Inhibiting Microglial Activation. In International journal of molecular sciences, 22, . doi:10.3390/ijms22115657. https://pubmed.ncbi.nlm.nih.gov/34073390/

4. Gu, Li, Zhu, Yahui, Lin, Xi, Prochownik, Edward V, Li, Youjun. 2020. The IKKβ-USP30-ACLY Axis Controls Lipogenesis and Tumorigenesis. In Hepatology (Baltimore, Md.), 73, 160-174. doi:10.1002/hep.31249. https://pubmed.ncbi.nlm.nih.gov/32221968/

5. Krazinski, Bartlomiej E, Kowalczyk, Anna E, Sliwinska-Jewsiewicka, Agnieszka, Kmiec, Zbigniew, Kiewisz, Jolanta. 2018. IKBKB expression in clear cell renal cell carcinoma is associated with tumor grade and patient outcomes. In Oncology reports, 41, 1189-1197. doi:10.3892/or.2018.6872. https://pubmed.ncbi.nlm.nih.gov/30483769/

6. Wang, Xiongjun, Liu, Ruilong, Qu, Xiujuan, Li, Guohui, Yang, Weiwei. 2019. α-Ketoglutarate-Activated NF-κB Signaling Promotes Compensatory Glucose Uptake and Brain Tumor Development. In Molecular cell, 76, 148-162.e7. doi:10.1016/j.molcel.2019.07.007. https://pubmed.ncbi.nlm.nih.gov/31447391/

7. Cao, Yumei, Tang, Su'an, Nie, Xiaoyu, Zhu, Zhaohua, Ding, Changhai. 2021. Decreased miR-214-3p activates NF-κB pathway and aggravates osteoarthritis progression. In EBioMedicine, 65, 103283. doi:10.1016/j.ebiom.2021.103283. https://pubmed.ncbi.nlm.nih.gov/33714889/

8. Schmid, Johannes A, Birbach, Andreas. 2008. IkappaB kinase beta (IKKbeta/IKK2/IKBKB)--a key molecule in signaling to the transcription factor NF-kappaB. In Cytokine & growth factor reviews, 19, 157-65. doi:10.1016/j.cytogfr.2008.01.006. https://pubmed.ncbi.nlm.nih.gov/18308615/

9. Cardinez, Chelisa, Miraghazadeh, Bahar, Tanita, Kay, Kanegane, Hirokazu, Cook, Matthew C. 2018. Gain-of-function IKBKB mutation causes human combined immune deficiency. In The Journal of experimental medicine, 215, 2715-2724. doi:10.1084/jem.20180639. https://pubmed.ncbi.nlm.nih.gov/30337470/