Identification of PP1 as the First Phosphatase for IRF7
1Center of Excellence for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, USA
2Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, USA
- *Corresponding Author:
- Shunbin Ning
Center of Excellence for Inflammation, Infectious Diseases and Immunity
Quillen College of Medicine, East Tennessee State
University, Johnson City, USA
E-mail: [email protected]
Received date: March 13, 2017; Accepted date: April 11, 2017; Published date: April 19, 2017
Citation: Ning S (2017) Identification of PP1 as the First Phosphatase for IRF7. J Cell Signal 2:146.
Copyright: © 2017 Ning S. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Interferon (IFN) regulatory factor 7 (IRF7) is phosphorylated and
activated in response to pathogenic infections for production of type I
IFNs. The IFN production has to be turned off soon after infection.
While there are a panel of kinases have been identified for IRF7
phosphorylation, no phosphatase has been reported for IRF7
dephosphorylation that may play a pivotal role in turning off IFN
production. We have recently addressed this critical question by
identification of protein phosphatase 1 (PP1) as the first phosphatase
Main content: The host innate immune system defends against
invading pathogens initially by triggering signaling pathways mediated
by the transmembrane receptors TLRs , and cytoplasmic receptors
that include RLRs [2,3], NLRs , cGAS [5,6], IFI16 , DDX41 [8,9],
DHX9/36 [10,11], RNA polymerase III , TRIM5α , ISG56 ,
LRRFIP1 , MRE11 , amongst others. Interferon (IFN)
regulatory factor 7 (IRF7) is phosphorylated and activated downstream
of many of these innate immune pathways for induction of IFN-I gene
expression (especially IFNαs) . The innate immune system also
comprises of lymphocytes-mediated epigenetic memory, which
defends reinfection and involves ATF7-mediated chromatin regulation
IRF7 is required not only for IFN priming at early stage, but also for
IFN amplification at later stages when robust IFN-I production
depends on a positive regulatory circuit between IRF7 and IFN-I
[20-22]. This robust reaction is turned off soon after infection under
normal physiological conditions, but excessive production of IFN-I is
fatal to the cell. Thus, regulation of IRF7 phosphorylation is of
paramount importance for controlling antiviral innate immunity.
However, no phosphatase for negative regulation of IRF7
phosphorylation and activity has been reported.
In our recent study , we have identified a conserved protein
phosphatase 1 (PP1)-binding motif in human and mouse IRF7
proteins, and shown that PP 1 physically interacts with IRF7.
Exogenous expression of PP1 subunits (PP1α, β or γ) ablates IKKε-
stimulated IRF7 phosphorylation and dramatically attenuates IRF7
transcriptional activity. Inhibition of PP1 activity significantly
increases IRF7 phosphorylation and IRF7-mediated IFNα production
in response to NDV infection or Toll-like receptor 7 (TLR7) challenge,
leading to impaired viral replication. In addition, IFN treatment, TLR
challenges and viral infection induce PP1 expression.
Our results are the first to identify PP1 as a phosphatase that targets
key activating phosphorylation sites of IRF7, attenuating its activity
and blocking the IFN-I response during viral infection (Figure 1).
Thus, our study has addressed an important knowledge gap regarding
IRF7-mediated IFN-I innate immune response, and has broad
significance in IFN-mediated antiviral innate immunity and IRF7-
mediated pathogenesis . In future follow-up studies, we will
validate our findings in in vivo systems, and develop strategies to
control PP1 phosphatase activity during viral infection for potential
Figure 1: PP1 abrogates IRF7-mediated type I IFN response in
antiviral immunity. IRF7 is phosphorylated by IKKs or IRAK1
downstream of TLR signaling pathways in response to viral
infection. PP1 targets IRF7 for dephosphorylation and attenuates
type I IFN production in these signaling pathways. In addition, PP1
promotes IL6 production. In addition, IFN treatment, TLR
challenges and viral infection induce PP1 expression.
Correspondingly, we have identified IFN-responsive elements and
IRF-binding motifs in the PP1 gene promoters, and the
transcriptional regulation is currently under investigated.
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