Ciita, known as the MHC class II transactivator, is a master regulator of MHC class II (MHC-II) gene transcription. As a member of the NLR (nucleotide-binding domain, leucine-rich-repeat containing) protein family, it plays a crucial role in the activation and regulation of adaptive immunity through antigen presentation to CD4+ T cells [1,2,3]. CIITA also has a unique position as a regulator of both intrinsic and adaptive immunity [2].

FBXO11, an E3 ligase, has been shown to regulate CIITA protein level through ubiquitination-mediated degradation, thereby influencing MHC-II expression. FBXO11-deficient cells display increased levels of MHC-II and related genes, and its expression is negatively correlated with MHC-II in normal and cancer tissues [1]. In a rat model of Parkinson's disease, reduced Ciita levels significantly increase α-Syn pathology, nigrostriatal neurodegeneration, and behavioral deficits. Ciita regulates susceptibility to PD-like pathology through changes in resident and peripheral immune cells and TNF levels [4]. In a Chinese family and unrelated endometriosis patients, novel missense variants of CIITA were identified, and one variant significantly affected cell migration and invasion ability, suggesting CIITA variants may contribute to endometriosis development [5].

In conclusion, Ciita is essential for regulating MHC-II gene expression and has a significant impact on immune-related processes. Its role in diseases such as Parkinson's disease and endometriosis has been revealed through model-based research, highlighting its importance in understanding disease mechanisms and potentially developing new treatment strategies.

References:

1. Kasuga, Yusuke, Ouda, Ryota, Watanabe, Masashi, Hatakeyama, Shigetsugu, Kobayashi, Koichi S. 2023. FBXO11 constitutes a major negative regulator of MHC class II through ubiquitin-dependent proteasomal degradation of CIITA. In Proceedings of the National Academy of Sciences of the United States of America, 120, e2218955120. doi:10.1073/pnas.2218955120. https://pubmed.ncbi.nlm.nih.gov/37279268/

2. Forlani, Greta, Shallak, Mariam, Gatta, Andrea, Shaik, Amruth K B, Accolla, Roberto S. 2023. The NLR member CIITA: Master controller of adaptive and intrinsic immunity and unexpected tool in cancer immunotherapy. In Biomedical journal, 46, 100631. doi:10.1016/j.bj.2023.100631. https://pubmed.ncbi.nlm.nih.gov/37467968/

3. León Machado, Jorge Alfonso, Steimle, Viktor. 2021. The MHC Class II Transactivator CIITA: Not (Quite) the Odd-One-Out Anymore among NLR Proteins. In International journal of molecular sciences, 22, . doi:10.3390/ijms22031074. https://pubmed.ncbi.nlm.nih.gov/33499042/

4. Fredlund, Filip, Jimenez-Ferrer, Itzia, Grabert, Kathleen, Luk, Kelvin, Swanberg, Maria. . Ciita Regulates Local and Systemic Immune Responses in a Combined rAAV-α-synuclein and Preformed Fibril-Induced Rat Model for Parkinson's Disease. In Journal of Parkinson's disease, 14, 693-711. doi:10.3233/JPD-240062. https://pubmed.ncbi.nlm.nih.gov/38728204/

5. Zhu, Ying, Pan, Hong, Han, Yang, Liu, Kaijiang, Wang, Binbin. 2022. Novel missense variant of CIITA contributing to endometriosis. In Reproductive biomedicine online, 45, 544-551. doi:10.1016/j.rbmo.2022.05.011. https://pubmed.ncbi.nlm.nih.gov/35835655/