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 3

ZDHHC12 associates with MAVS.

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ZDHHC12 associates with MAVS. (A) HEK293T cells were transfected with HA...
(A) HEK293T cells were transfected with HA-ZDHHC12, together with indicated plasmids, respectively, for 24 hours. Cell extracts were collected for immunoprecipitation (IP) and immunoblot analysis. WCL, whole-cell lysates. Asterisks indicate nonspecific anti-FLAG reactive bands. (B and C) THP-1–derived macrophages were treated with SeV (MOI = 1) (B) or IC poly(I:C) (5 μg/mL) (C) for indicated time periods. Cell lysates were collected for IP and immunoblot analysis to detect the endogenous MAVS-ZDHHC12 association. (D) HEK293T cells were transfected with plasmids expressing CFP-MAVS as a fluorescence resonance energy transfer (FRET) donor and YFP-ZDHHC12 as a FRET acceptor for 24 hours, followed by infection of SeV (MOI = 1) for 12 hours. The interaction between MAVS and ZDHHC12 was determined by a FRET-based protein-protein interaction assay. (E) Top: Domain organization of MAVS protein. Bottom: IP and immunoblot analysis of extracts of HEK293T cells transfected with plasmids encoding HA-ZDHHC12 together with indicated plasmids for 24 hours. (F) Top: Domain organization of ZDHHC12 protein. Bottom: IP and immunoblot analysis of extracts of HEK293T cells transfected with plasmids encoding HA-MAVS together with indicated plasmids for 24 hours. Asterisks indicate nonspecific anti-FLAG reactive bands. In A–C, E, and F, similar results were obtained for 3 independent experiments. In D, data are presented as mean values ± SD. Statistical analysis was performed using 2-tailed Student’s t test.