DNAJB1/HSP40 Suppresses Melanoma Differentiation-Associated Gene 5-Mitochondrial Antiviral Signaling Protein Function in Conjunction with HSP70.

Abstract:

:Melanoma differentiation-associated gene 5 (MDA5) is a pattern recognition receptor that recognizes cytoplasmic viral double-stranded RNA (dsRNA) and initiates rapid innate antiviral responses. MDA5 forms a filament-like multimer along the dsRNA leading to oligomerization, which in turn activates the adaptor protein mitochondrial antiviral signaling protein (MAVS) to provide a signal platform for the induction of type I interferon (IFN) and proinflammatory cytokines. The conformational switch of MDA5 causes antiviral defense, but excessive activation of the MDA5-MAVS pathway may result in autoimmune diseases. The regulatory mechanisms of MDA5 activation remain largely unknown. By yeast 2-hybrid, we identified DNAJB1, a member of the HSP40 (heat shock protein 40) family, as an MDA5-binding protein. HSP40s usually cowork with HSP70s. We found that dsRNA stimulation with physiological conditions upregulated the expression levels of DNAJB1 and HSP70; then the proteins were coupled and translocated into the stress granules, where MDA5 encounters dsRNA. DNAJB1 disrupted MDA5 multimer formation, resulting in the suppression of type I IFN induction. The disruption of endogenous DNAJB1 increased MDA5- and MAVS-mediated IFN promoter activation and rendered cells virus resistant. HSP70 inhibitor also enhanced the IFN-inducing function of MDA5 and MAVS. These results suggest that the DNAJB1-HSP70 complex functions for the natural maintenance of RNA sensing by interacting with MDA5/MAVS.

journal_name

J Innate Immun

authors

Takashima K,Oshiumi H,Matsumoto M,Seya T

doi

10.1159/000480740

subject

Has Abstract

pub_date

2018-01-01 00:00:00

pages

44-55

issue

1

eissn

1662-811X

issn

1662-8128

pii

000480740

journal_volume

10

pub_type

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