Fig 2: A hypothetical model for differential MAVS placement regulating metabolism and innate immunity.In RLR signaling, MAVS translocated to peroxisomes and recruits G6PD, leading to the activation of the PPP. Then, TRAF6 and IRF1 interact with MAVS initiating signaling cascades that lead to the production of type III IFN. Conversely, MAVS translocated to MAMs and recruits GFPT2, leading to the activation of the HBP. Then, TRAF6, and TRAF2 interact with MAVS, leading to the production of type I IFN (a) (Fig. 9a). When PPP and HBP are inhibited by drugs (b) (Fig. 9b), phosphorylation of TBK1 and IRF3 downstream of MAVS is inhibited, resulting in a decrease of the respective IFN responses. Red arrows indicate early metabolic changes. Black arrows indicate later IFN production. The thickness of the arrow represents the enhancement or weakening of the reaction.

Fig 3: The specific subcellular localization of MAVS regulates different signaling pathways via the recruitment of GFPT2/TRAF6/TRAF2 or G6PD/TRAF6/IRF1.a–c Mavs−/− BMDMs were transfected with a control vector or indicated MAVS alleles for 48 h. Co-IP and immunoblot analyses (a, c) and Western blot analyses (b) were performed with the indicated antibodies. d, e Mavs−/− BMDMs were transfected with the control vector or indicated MAVS alleles for 48 h, followed by an analysis of G6PD activity (d) or G6PD dimerization (e) (n = 3 mice per condition, means ± SEMs, one-way ANOVA). f Mavs−/− BMDMs were transfected with the control vector or indicated MAVS alleles for 48 h. Subcellular fractions were isolated for immunoblot analysis. Fractionation markers: mitochondria (Tom40); MAMs (FACL4); peroxisomes (Pex19); cytosol (Tubulin). g Mavs−/− BMDMs were transfected with NF-κB-luc and indicated MAVS alleles for 48 h before luciferase assays. h, i Experiments were performed similar to those in (g), except ISRE-luc (h) or IRF1-luc (i) were used. j, k Mavs−/− BMDMs were transfected with si-ctrl, si-GFPT2, si-G6PD, or indicated MAVS alleles for 36 h before qPCR analyses. Data in (a–c, f) are representative from three independent experiments. Data in (g–k) are presented as means ± SEMs, n = 3 mice per condition, two-way ANOVA. See also Supplementary Fig. 14. Source data are provided as a Source Data file.