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 6

Palmitoylation is essential for MAVS aggregation.

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Palmitoylation is essential for MAVS aggregation. (A) Immunoblot and SDD...
(A) Immunoblot and SDD-AGE analysis in MAVS-KO HEK293T cells transfected with indicated plasmids and infected with SeV. (B) The colocalization between MAVS and TOMM20 was examined by confocal microscopy. Scale bars: 10 μm. (C) Quantification of MAVS aggregates of B (30 cells per sample). (D) The MAVS-TOMM20 colocalization was quantified by Pearson’s correlation coefficient. (E and F) MAVS-KO (E) or WT (F) HEK293T cells were transfected with indicated plasmids, followed by SeV infection. Cell lysates were collected for luciferase reporter assays (E) and SDD-AGE analysis (F). (G and H) The indicated cells were infected with SeV for indicated time periods. Cell lysates were collected for immunoblot analysis and SDD-AGE analysis. (I) Immunoblot analysis and SDD-AGE analysis in indicated BMDMs transfected with indicated plasmids, followed by infection with SeV. (J and K) MAVS-KO HEK293T cells were transfected with indicated plasmids, then infected with SeV. Cell extracts were harvested for SDD-AGE (J) and IP analysis (K). (L and M) MAVS-KO HEK293T cells were transfected with the indicated plasmids, and then infected without (L) or with SeV (M). The MAVS-MAVS interaction was determined by FRET assay (M). Cell lysates were collected for immunoblot analysis. (N) PyMOL software (https://www.pymol.org/) was used to determine the interaction locations of monomer MAVS CARD (A and B) and the palmitoylation site MAVS C79 in monomer MAVS CARD (A). (O) Cartoon of potential cooperativity between palmitoylation of MAVS CARD domain during growth of the MAVS prion-like aggregates. In A and F–L, 3 independent experiments yielded similar results. In C, D, and M, data are presented as mean values ± SD. In E, data are presented as mean values ± SEM. Statistical analysis was performed using 1-way ANOVA multiple comparisons in C–E and M.