Rubicon Modulates Antiviral Type I Interferon (IFN) Signaling by Targeting IFN
Regulatory Factor 3 Dimerization
#MMPMID28468885
Kim JH
; Kim TH
; Lee HC
; Nikapitiya C
; Uddin MB
; Park ME
; Pathinayake P
; Lee ES
; Chathuranga K
; Herath TUB
; Chathuranga WAG
; Lee JS
J Virol
2017[Jul]; 91
(14
): ? PMID28468885
show ga
Rubicon is part of a Beclin-1-Vps34-containing autophagy complex. Rubicon induces
antimicrobial responses upon Toll-like receptor (TLR) stimulation and functions
as a feedback inhibitor to prevent unbalanced proinflammatory responses depending
on dectin-1 signaling. However, the role played by Rubicon during antiviral
immune responses, particularly the type I interferon (IFN) responses, remains
largely unknown. Here, we report that Rubicon acts as a negative regulator for
virus-triggered IFN signaling. Knockdown of Rubicon promoted type I interferon
signaling and inhibited virus replication, while overexpression of Rubicon had
the opposite effect. Rubicon specifically interacts with the interferon
regulatory factor (IRF) association domain (IAD) of IRF3, and this interaction
leads to inhibition of the dimerization of IRF3, which negatively regulates
IFN-mediated antiviral response. Thus, our findings suggest the novel additional
role of Rubicon as a negative regulator that inhibits the IFN signaling and
cellular antiviral responses, providing a novel cellular mechanism of IRF3
inhibition.IMPORTANCE The type I IFN system is a critical innate immune response
that protects organisms against virus infection. However, type I IFN signaling
must be tightly regulated to avoid excessive production of IFNs. Hence, negative
regulatory mechanisms for type I IFN signaling are important, and to date,
several related molecules have been identified. Here, we show that Rubicon is a
major negative regulator of type I IFN signaling, and unlike previous reports of
cellular molecules that inhibit IRF3 activation via proteasomal degradation or
dephosphorylation of IRF3, we show that Rubicon interacts with IRF3 and that
ultimately this interaction leads to inhibition of the dimerization of IRF3.
Thus, we identified a novel negative regulator of type I IFN signaling pathways
and a novel cellular mechanism of IRF3 inhibition. The results of this study will
increase our understanding of the role of negative-feedback mechanisms that
regulate type I IFN signaling and maintain immune homeostasis.
|*Protein Multimerization
[MESH]
|*Signal Transduction
[MESH]
|Animals
[MESH]
|Influenza A Virus, H1N1 Subtype/*immunology
[MESH]
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