ZFYVE1 negatively regulates MDA5- but not RIG-I-mediated innate antiviral response.

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.

journal_name

PLoS Pathog

journal_title

PLoS pathogens

authors

Zhong X,Feng L,Zang R,Lei CQ,Yang Q,Shu HB

doi

10.1371/journal.ppat.1008457

subject

Has Abstract

pub_date

2020-04-06 00:00:00

pages

e1008457

issue

4

eissn

1553-7366

issn

1553-7374

pii

PPATHOGENS-D-19-01882

journal_volume

16

pub_type

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