Correspondence to Author:  Juliang Qin, 

Bing Du, Ph.D., Shanghai Key Laboratory of Regulatory Biology and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.

Abstract:

Emerging evidence suggests that GPCRs play a pivotal role in virus infection. However, the mechanisms underlying GPCRs-mediated type I interferon responses to protect host from viral infection are not systematically explored. In order to screen key functioning GPCRs in interferon induced expression process, we applied gene chips analysis, where the GPR109A, ranked as the uppermost regulated GPCR, functions as a powerful antiviral factor, implicating its potential role as an antivirus target. The expression of GPR109A was upregulated in mouse peritoneal macrophages (PEM) stimulated with IFNβ, IFNγ and virus, as determined by Q-PCR and Western blot analysis. Moreover, blocking STAT1 activation using inhibitor (Fludarabine) could decrease the expression of GPR109A expression induced by IFNβ and IFNγ stimulation. Above results suggested that GPR109A is an interferon-stimulated gene (ISG). Both VSV-virus infection and replication was remarkably enhanced in Gpr109a-/- macrophage compared to the WT macrophage. GPR109A deficiency reduced the survival of VSV-virus infection lethal mouse model with increased virus infection rate of peritoneal cells, and increased virus titers in various abdominal organs were observed. Mechanistically, increased viral infection in GPR109A deficient mouse was due to reduced IFN production by restraining the formation of autophagosomes. This is confirmed by an activation of autophagy in GPR109A deficient cells, where normal IFN production was restored. Finally, nicotinic acid induced the formation of autophagosomes in GPR109A dependent manner, and further increased the release of IFN, which contributed to the anti-VSV infection, implying the clinical potential of GPR109A in antiviral infection treatment.

Keywords:GPR109A, viral infection, ISGs, IFN-I, autophagy

Citation:

Juliang Qin. Nicotinic acid receptor GPR109A promotes antiviral innate immune response through autophagy. Journal of Immunology 2024.