OTULIN, also known as OTU deubiquitinase with linear linkage specificity, is a crucial deubiquitinating enzyme. It regulates inflammation and cell death by hydrolyzing linear ubiquitin chains generated by the linear ubiquitin chain assembly complex (LUBAC) [1,2]. It is involved in pathways like NF-κB signaling, and its proper function is vital for maintaining normal inflammatory responses and preventing chronic inflammation and disease [2,3].

Loss-of-function mutations in OTULIN have been extensively studied. Biallelic loss-of-function mutations cause OTULIN-related autoinflammatory syndrome (ORAS). In ORAS patient cells, there is an accumulation of linear ubiquitin chains, increased sensitivity to TNF-induced death, and dysregulation of inflammatory signaling [1]. Myeloid-specific OTULIN-deficient mice show that OTULIN deficiency licenses RIPK3-mediated cell death in macrophages, leading to Nlrp3 inflammasome activation and IL-1β secretion [4]. OTULIN haploinsufficiency in humans impairs cell-intrinsic immunity to staphylococcal α-toxin, making patients susceptible to life-threatening staphylococcal infections [5].

In conclusion, OTULIN plays essential roles in controlling inflammation and cell death through its regulation of linear ubiquitin chains. Studies using gene-knockout models, especially in mice, have revealed its significance in autoinflammatory syndromes and susceptibility to certain infections. Understanding OTULIN's functions provides insights into the mechanisms of immune-related diseases and may offer potential therapeutic targets [1,4,5].

References:

1. Davidson, Sophia, Shibata, Yuri, Collard, Sophie, Komander, David, Masters, Seth L. 2024. Dominant negative OTULIN-related autoinflammatory syndrome. In The Journal of experimental medicine, 221, . doi:10.1084/jem.20222171. https://pubmed.ncbi.nlm.nih.gov/38630025/

2. Verboom, Lien, Hoste, Esther, van Loo, Geert. 2021. OTULIN in NF-κB signaling, cell death, and disease. In Trends in immunology, 42, 590-603. doi:10.1016/j.it.2021.05.003. https://pubmed.ncbi.nlm.nih.gov/34074601/

3. Wang, Qianhui, Wang, Lvxia, Botchway, Benson O A, Huang, Min, Liu, Xuehong. 2024. OTULIN Can Improve Spinal Cord Injury by the NF-κB and Wnt/β-Catenin Signaling Pathways. In Molecular neurobiology, 61, 8820-8830. doi:10.1007/s12035-024-04134-3. https://pubmed.ncbi.nlm.nih.gov/38561559/

4. Doglio, M Giulia, Verboom, Lien, Ruilova Sosoranga, Emily, van Loo, Geert, Wullaert, Andy. 2023. Myeloid OTULIN deficiency couples RIPK3-dependent cell death to Nlrp3 inflammasome activation and IL-1β secretion. In Science immunology, 8, eadf4404. doi:10.1126/sciimmunol.adf4404. https://pubmed.ncbi.nlm.nih.gov/38000038/

5. Spaan, András N, Neehus, Anna-Lena, Laplantine, Emmanuel, Boisson, Bertrand, Casanova, Jean-Laurent. 2022. Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin. In Science (New York, N.Y.), 376, eabm6380. doi:10.1126/science.abm6380. https://pubmed.ncbi.nlm.nih.gov/35587511/