Abstract
Osteopontin (OPN) is a multifunctional protein involved in both innate immunity and adaptive immunity. However, the function of OPN, especially the intracellular form OPN (iOPN) on innate antiviral immune response remains elusive. Here, we demonstrated that iOPN is an essential positive regulator to protect the host from virus infection. OPN deficiency or knockdown significantly attenuated virus-induced IRF3 activation, IFN-β production and antiviral response. Consistently, OPN-deficient mice were more susceptible to VSV infection than WT mice. Mechanistically, iOPN was found to interact with tumor necrosis factor receptor (TNFR)-associated factor 3 (TRAF3) and inhibit Triad3A-mediated K48-linked polyubiquitination and degradation of TRAF3 through the C-terminal fragment of iOPN. Therefore, our findings delineated a new function for iOPN to act as a positive regulator in innate antiviral immunity through stabilization of TRAF3.
Highlights
The innate immunity is the first line of defense against invading pathogens, which functions to respond to infection directly and relays signals for the activation of the adaptive immunity[1]
Expression plasmid or control vector for 24 h, the cells were pretreated with OPN specific antibody or control IgG for 4 h, and infected with Sendai virus (SeV) for 16 h. (H) Luciferase activity in HEK293 cells transfected with expression plasmids for IFN-β promoter reporter, retinoic acid–inducible gene I (RIG-I), melanoma differentiation-associated gene 5 (MDA5), TRIF or stimulator of interferon genes protein (STING)+ cGAS together with increasing amount of intracellular form OPN (iOPN) plasmid
To investigate whether OPN is involved in antiviral response, OPN expression was measured in murine peritoneal macrophages infected with Sendai virus (SeV) and vesicular stomatitis virus (VSV), which have been shown to trigger the RIG-I signaling
Summary
The innate immunity is the first line of defense against invading pathogens, which functions to respond to infection directly and relays signals for the activation of the adaptive immunity[1]. Several classes of germline-encoded pattern-recognition receptors (PRRs) have been linked to the production of type I interferons during viral infection These PRRs include Toll-like receptors (TLRs), retinoic acid–inducible gene I (RIG-I) like receptor (RLRs) and intracellular DNA sensors[3,4,5]. The function of iOPN in innate antiviral immune response is not known
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