Ifngr1, encoding the interferon gamma receptor 1, is a key component of the interferon-γ (IFNγ) receptor complex. IFNγ signals through a tetramer of two IFN-γR1 chains in complex with two IFN-γR2 chains, where IFN-γR1 is the ligand-binding chain. The IFNγ signaling pathway is essential for the innate immune defense against mycobacterial infections and plays a crucial role in various immune-related biological processes [4]. Genetic models, such as gene knockout (KO) mouse models, are valuable for studying its functions.

In murine cancer models, loss of optineurin was shown to attenuate IFNGR1 expression, impair T-cell immunity, and diminish immunotherapy efficacy. Mechanistically, IFNGR1 was S-palmitoylated, and AP3D1 sorted palmitoylated IFNGR1 to lysosome for degradation, while optineurin interacted with AP3D1 to prevent this degradation [1]. In macrophages following myocardial infarction, RNF149, a highly expressed E3 ubiquitin ligase, promoted ubiquitylation-dependent proteasomal degradation of IFNGR1. Knockout of RNF149 exacerbated cardiac dysfunction, and loss of IFNGR1 rescued the deleterious effects of RNF149 deficiency [2]. Blocking sphingolipid production in cancer cells increased surface levels of IFNGR1, enhancing the anti-proliferative effects of immune cells via IFNγ signalling [3].

In conclusion, Ifngr1 is fundamental for IFNγ-mediated immune responses. Model-based research, especially KO mouse models, has revealed its significance in cancer immune evasion, post-infarction cardiac repair, and tuberculosis susceptibility. Understanding Ifngr1's functions provides insights into immune-related disease mechanisms and potential therapeutic targets.

References:

1. Du, Wan, Hua, Fang, Li, Xiong, Fang, Jing-Yuan, Zou, Weiping. 2021. Loss of Optineurin Drives Cancer Immune Evasion via Palmitoylation-Dependent IFNGR1 Lysosomal Sorting and Degradation. In Cancer discovery, 11, 1826-1843. doi:10.1158/2159-8290.CD-20-1571. https://pubmed.ncbi.nlm.nih.gov/33627378/

2. Huang, Chun-Kai, Chen, Zhiyong, Zhou, Zhongxing, Yan, Xiaoxiang, Chai, Dajun. 2024. RNF149 Destabilizes IFNGR1 in Macrophages to Favor Postinfarction Cardiac Repair. In Circulation research, 135, 518-536. doi:10.1161/CIRCRESAHA.123.324023. https://pubmed.ncbi.nlm.nih.gov/38989590/

3. Soula, Mariluz, Unlu, Gokhan, Welch, Rachel, Beyaz, Semir, Birsoy, Kıvanç. 2024. Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer. In Nature, 633, 451-458. doi:10.1038/s41586-024-07787-1. https://pubmed.ncbi.nlm.nih.gov/39112706/

4. van de Vosse, Esther, van Dissel, Jaap T. 2017. IFN-γR1 defects: Mutation update and description of the IFNGR1 variation database. In Human mutation, 38, 1286-1296. doi:10.1002/humu.23302. https://pubmed.ncbi.nlm.nih.gov/28744922/