Abstract
The retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), including RIG-I and melanoma differentiation-associated gene 5 (MDA5), sense cytoplasmic viral RNA and initiate innate antiviral responses. How RIG-I and MDA5 are differentially regulated remains enigmatic. In this study, we identified the guanylate-binding protein (GBP) and zinc-finger FYVE domain-containing protein ZFYVE1 as a negative regulator of MDA5- but not RIG-I-mediated innate antiviral responses. ZFYVE1-deficiency promoted MDA5- but not RIG-I-mediated transcription of downstream antiviral genes. Comparing to wild-type mice, Zfyve1-/- mice were significantly protected from lethality induced by encephalomyocarditis virus (EMCV) that is sensed by MDA5, whereas Zfyve1-/- and Zfyve1+/+ mice were comparable to death induced by vesicular stomatitis virus (VSV) that is sensed by RIG-I. Mechanistically, ZFYVE1 interacted with MDA5 but not RIG-I. ZFYVE1 bound to viral RNA and decreased the ligand binding and oligomerization of MDA5. These findings suggest that ZFYVE1 acts as a specific negative regulator of MDA5-mediated innate immune responses by inhibiting its ligand binding and oligomerization.
Highlights
The innate immune system is the first line of host defense against microbial infection
Comparing to wild-type mice, Zfyve1-/mice were significantly protected from lethality induced by encephalomyocarditis virus (EMCV) that is sensed by melanoma differentiation-associated gene 5 (MDA5), whereas Zfyve1-/- and Zfyve1+/+ mice were comparable to death induced by vesicular stomatitis virus (VSV) that is sensed by retinoic acid-inducible gene-I (RIG-I)
Our study reveals a negative regulatory mechanism for keeping MDA5 inactive in un-infected cells, which contributes to our understanding on how innate antiviral responses are delicately regulated to avoid immune damage
Summary
The animal care and use were adhered to the Chinese National Guidelines for Ethical Review of Animal Welfare. The protocols and procedures for mice experiments in this study were approved by the Wuhan University College of Life Sciences Animal Care and Use Committee (approval number WDSKY0200902-2). Zfyve1+/+ and Zfyve1-/- MLFs were transfected with poly(I:C)-HMW (4 μg/ml) for the indicated times. Cell lysates were fractionated by SDD-AGE or SDS-PAGE and analyzed by immunoblots with the indicated antibodies. Data are representative of three biological replicates (A-E) with similar results
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