Palmitoylation acts as a checkpoint for MAVS aggregation to promote antiviral innate immune responses
Liqiu Wang, … , Yaoxing Wu, Jun Cui
Liqiu Wang, … , Yaoxing Wu, Jun Cui
Published December 2, 2024
Citation Information: J Clin Invest. 2024;134(23):e177924. https://doi.org/10.1172/JCI177924.
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Research Article Cell biology Immunology

Palmitoylation acts as a checkpoint for MAVS aggregation to promote antiviral innate immune responses

Abstract

Upon RNA virus infection, the signaling adaptor MAVS forms functional prion-like aggregates on the mitochondrial outer membrane, which serve as a central hub that links virus recognition to downstream antiviral innate immune responses. Multiple mechanisms regulating MAVS activation have been revealed; however, the checkpoint governing MAVS aggregation remains elusive. Here, we demonstrated that the palmitoylation of MAVS at cysteine 79 (C79), which is catalyzed mainly by the palmitoyl S-acyltransferase ZDHHC12, was essential for MAVS aggregation and antiviral innate immunity upon viral infection in macrophages. Notably, the systemic lupus erythematosus–associated mutation MAVS C79F was associated with defective palmitoylation, resulting in low type I interferon (IFN) production. Accordingly, Zdhhc12 deficiency apparently impaired RNA virus–induced type I IFN responses, and Zdhhc12-deficient mice were highly susceptible to lethal viral infection. These findings reveal a previously unknown mechanism by which the palmitoylation of MAVS is a checkpoint for its aggregation during viral infection to ensure timely activation of antiviral defense.

Authors

Liqiu Wang, Mengqiu Li, Guangyu Lian, Shuai Yang, Jing Cai, Zhe Cai, Yaoxing Wu, Jun Cui

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Figure 4

ZDHHC12 deficiency impairs cellular antiviral responses.

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ZDHHC12 deficiency impairs cellular antiviral responses. (A and B) WT (...
(A and B) WT (sgCtrl) or ZDHHC12-KO (sgZDHHC12#1/#2) THP-1 macrophages were treated with SeV for indicated time periods. Cell lysates were collected for immunoblot and real-time qPCR analysis. (C) WT or ZDHHC12-KO THP-1 macrophages were treated with SeV or IC poly(I:C). IFN-β release was determined by ELISA. (D–F) BMDMs isolated from Zdhhc12+/+ or Zdhhc12–/– mice were treated with SeV for indicated time periods. Cell lysates were collected for immunoblot (D) and real-time qPCR analysis (E). IFN-β release was determined by ELISA (F). (G) Volcano plot of differentially expressed genes in BMDMs isolated from Zdhhc12+/+ or Zdhhc12–/– mice with SeV infection (MOI = 1, 12 hours). (H) Gene Ontology enrichment analysis of the genes in G. (I) Heatmap view of mRNA variations of type I IFN–mediated ISG sets in BMDMs from Zdhhc12+/+ or Zdhhc12–/– mice with SeV infection. (J and K) Immunoblot (J) and ELISA analysis (K) in Zdhhc12+/+ or Zdhhc12–/– BMDMs transfected with empty vector (EV) or plasmid encoding ZDHHC12 using jetPRIME for 48 hours, followed by infection with SeV for 12 hours. (L–O) The human PBMCs were transfected with siCtrl or siZDHHC12 for 48 hours and infected with SeV or IC poly(I:C) for indicated time periods. Cell lysates were collected for immunoblot (L and M) and real-time qPCR analysis (N and O). (P) WT or ZDHHC12-knockdown PBMCs were treated with SeV or IC poly(I:C). IFN-β release was determined by ELISA. In A, D, G–J, L, and M, similar results were obtained for 3 independent experiments. In B, C, E, F, K, O, and P, data are presented as mean values ± SEM. Statistical analysis was performed using 2-tailed Student’s t test in E, F, O, and P or 1-way ANOVA multiple comparisons in B, C, and K.