Palmitoylation acts as a checkpoint for MAVS aggregation to promote antiviral innate immune responses
Liqiu Wang, Mengqiu Li, Guangyu Lian, Shuai Yang, Jing Cai, Zhe Cai, Yaoxing Wu, Jun Cui
Liqiu Wang, Mengqiu Li, Guangyu Lian, Shuai Yang, Jing Cai, Zhe Cai, Yaoxing Wu, Jun Cui
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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 5

K63 ubiquitination of MAVS facilitates its palmitoylation.

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K63 ubiquitination of MAVS facilitates its palmitoylation. (A and B) HEK...
(A and B) HEK293T cells were transfected with indicated plasmids for 24 hours. Cell lysates were collected for IP and immunoblot analysis. (C and D) HEK293T cells were transfected with indicated plasmids for 24 hours. Cell lysates were collected for IP and immunoblot analysis. (E–H) IP and immunoblot analysis of WT (sgCtrl) or ZDHHC12-KO (sgZDHHC12) THP-1 macrophages (E and F) or BMDMs from Zdhhc12+/+ or Zdhhc12–/– mice (G and H) infected with SeV for 12 hours. (I) THP-1–derived macrophages were transfected with siCtrl or siTRIM31 for 48 hours, and then infected with SeV for 12 hours. Cell lysates were collected for immunoblot analysis, real-time qPCR analysis, IP analysis, and ABE assay. (J) HEK293T cells were transfected with indicated plasmids for 24 hours, followed by infection of SeV for 12 hours. Cell extracts were collected for IP and immunoblot analysis. (K) HEK293T cells were transfected with WT FLAG-MAVS or FLAG-MAVS K0 mutant in the presence of HA-ZDHHC12 or not for 24 hours, then infected with SeV for 12 hours. Cell lysates were collected for ABE assay and immunoblot analysis. In A–K, similar results were obtained for 3 independent experiments. In B, D, F, H, I, and K, data are presented as mean values ± SD. Statistical analysis was performed using 2-tailed Student’s t test in B, D, F, H, and I or 1-way ANOVA multiple comparisons in K.