NAD activates olfactory receptor 1386 to regulate type I interferon responses in Plasmodium yoelii YM infection

Olfactory receptors (Olfr) are G protein-coupled receptors that are normally expressed on olfactory sensory neurons to detect volatile chemicals or odorants. Interestingly, many Olfrs are also expressed in diverse tissues and function in cell-cell recognition, migration, and proliferation as well as...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 121; no. 23; p. e2403796121
Main Authors Peng, Yu-Chih, Wu, Jian, He, Xiao, Dai, Jin, Xia, Lu, Valenzuela-Leon, Paola, Tumas, Keyla C, Singh, Brajesh K, Xu, Fangzheng, Ganesan, Sundar, Munir, Shirin, Calvo, Eric, Huang, Ruili, Liu, Chengyu, Long, Carole A, Su, Xin-Zhuan
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 04.06.2024
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Summary:Olfactory receptors (Olfr) are G protein-coupled receptors that are normally expressed on olfactory sensory neurons to detect volatile chemicals or odorants. Interestingly, many Olfrs are also expressed in diverse tissues and function in cell-cell recognition, migration, and proliferation as well as immune responses and disease processes. Here, we showed that many Olfr genes were expressed in the mouse spleen, linked to genetic loci significantly, and/or had genome-wide patterns of LOD scores (GPLSs) similar to those of host Toll-like receptor genes. Expression of specific Olfr genes such as in HEK293T cells significantly increased luciferase signals driven by IFN-β and NF-κB promoters, with elevated levels of phosphorylated TBK1, IRF3, P38, and JNK. Mice without Olfr1386 were generated using the CRISPR/Cas9 method, and the mice showed significantly lower IFN-α/β levels and longer survival than wild-type (WT) littermates after infection with YM parasites. Inhibition of G protein signaling and P38 activity could affect cyclic AMP-responsive element promoter-driven luciferase signals and IFN-β mRNA levels in HEK293T cells expressing the Olfr1386 gene, respectively. Screening of malaria parasite metabolites identified nicotinamide adenine dinucleotide (NAD) as a potential ligand for Olfr1386, and NAD could stimulate IFN-β responses and phosphorylation of TBK1 and STAT1/2 in RAW264.7 cells. Additionally, parasite RNA (pRNA) could significantly increase mRNA levels. This study links multiple Olfrs to host immune response pathways, identifies a candidate ligand for Olfr1386, and demonstrates the important roles of Olfr1386 in regulating type I interferon (IFN-I) responses during malaria parasite infections.
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ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.2403796121