Abstract
The ubiquitin regulatory X domain-containing proteins (UBXNs) are likely involved in diverse biological processes. Their physiological functions, however, remain largely unknown. Here we present physiological evidence that UBXN3B positively regulates stimulator-of-interferon genes (STING) signaling. We employ a tamoxifen-inducible Cre-LoxP approach to generate systemic Ubxn3b knockout in adult mice as the Ubxn3b-null mutation is embryonically lethal. Ubxn3b−/−, like Sting−/− mice, are highly susceptible to lethal herpes simplex virus 1 (HSV-1) and vesicular stomatitis virus (VSV) infection, which is correlated with deficient immune responses when compared to Ubxn3b+/+ littermates. HSV-1 and STING agonist-induced immune responses are also reduced in several mouse and human Ubxn3b−/− primary cells. Mechanistic studies demonstrate that UBXN3B interacts with both STING and its E3 ligase TRIM56, and facilitates STING ubiquitination, dimerization, trafficking, and consequent recruitment and phosphorylation of TBK1. These results provide physiological evidence that links the UBXN family with antiviral immune responses.
Highlights
The ubiquitin regulatory X domain-containing proteins (UBXNs) are likely involved in diverse biological processes
We found that UBXN3B synergized with cGAMP to induce an IFN-I response in a dosedependent manner (Supplementary Fig. 1b and 1c)
To confirm that the enhancing effect on stimulator-of-interferon genes (STING) signaling was specific to UBXN3B, we included two UBXN members, UBXN3A which is the closest sibling of UBXN3B and UBXN9 which is more dissimilar from UBXN3B, in terms of domain structure[20]
Summary
The ubiquitin regulatory X domain-containing proteins (UBXNs) are likely involved in diverse biological processes Mechanistic studies demonstrate that UBXN3B interacts with both STING and its E3 ligase TRIM56, and facilitates STING ubiquitination, dimerization, trafficking, and consequent recruitment and phosphorylation of TBK1 These results provide physiological evidence that links the UBXN family with antiviral immune responses. STING could transmit signals from other DNA sensors such as DNA-dependent activator of IFN regulatory factors (IRFs), DEAD-Box helicase 41, DNA-dependent protein kinase, and IFN-γ-inducible protein 16; their function in IFN-I response is still controversial[12] Being such a central adaptor in the DNA sensing pathway, STING signaling is stringently regulated by post-translational modifications. By utilizing dual luciferase reporter system, we identify that UBXN3B is a positive regulator of STING and that UBXN3B complexes with STING and TRIM56 to potentiate STINGdependent innate immune responses
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