Ormdl3, short for ORM1 (yeast)-like protein 3, is an endoplasmic reticulum-resident transmembrane protein. It is one of three ORMDL proteins that integrate multiple signals to maintain sphingolipid homeostasis. Ormdl3 inhibits serine palmitoyl-CoA transferase, the rate-limiting enzyme for sphingolipid biosynthesis, and activates the ATF6α branch of the unfolded protein response, which is related to asthma-relevant pathways [1,2].

In allergic asthma models, overexpression of Ormdl3 decreases serum sphingolipids, increases inflammatory markers, airway remodeling, and airway hyperreactivity (AHR) in response to allergic stimuli, while Ormdl3 knockout mice are protected from developing Alternaria alternata-induced AHR, suggesting Ormdl3 has a critical role for smooth muscle contraction in this context [1]. In ulcerative colitis, knockdown of Ormdl3 in human monocyte-derived macrophages reduces interleukin-1β release, and in a dextran sodium sulfate-induced colitis mouse model, it shows reduced colitis severity, indicating its role in modulating inflammation [3].

In summary, Ormdl3 is crucial for maintaining sphingolipid homeostasis and is involved in the unfolded protein response. Gene knockout mouse models have revealed its significant roles in allergic asthma and ulcerative colitis, mainly through affecting sphingolipid metabolism and inflammatory responses, providing important insights into the pathogenesis of these diseases.

References:

1. Worgall, Tilla S. . Sphingolipids, ORMDL3 and asthma: what is the evidence? In Current opinion in clinical nutrition and metabolic care, 20, 99-103. doi:10.1097/MCO.0000000000000349. https://pubmed.ncbi.nlm.nih.gov/28030368/

2. Das, Sudipta, Miller, Marina, Broide, David H. 2017. Chromosome 17q21 Genes ORMDL3 and GSDMB in Asthma and Immune Diseases. In Advances in immunology, 135, 1-52. doi:10.1016/bs.ai.2017.06.001. https://pubmed.ncbi.nlm.nih.gov/28826527/

3. Sharma, Jyotsna, Khan, Shaziya, Singh, Nishakumari C, Mitra, Kalyan, Lahiri, Amit. 2024. ORMDL3 regulates NLRP3 inflammasome activation by maintaining ER-mitochondria contacts in human macrophages and dictates ulcerative colitis patient outcome. In The Journal of biological chemistry, 300, 107120. doi:10.1016/j.jbc.2024.107120. https://pubmed.ncbi.nlm.nih.gov/38417794/