On December 20th, 2016, researchers in Dr. Chunfu Zheng’s group published an article entitled “Herpes Simplex Virus Type 1 Ubiquitin-specific Protease UL36 abrogates NF-κB Activation in DNA Sensing Signal Pathway” in Journal of Virology. Our results show for the first time that herpes simplex virus type 1 (HSV-1) ubiquitin-specific protease (UL36USP), which is localized in the N terminus of the tegument protein UL36, antagonizes the DNA sensor induced NF-κB activation and IFN-β production by deubiquitinating IκBα. This study provides new insight into evasion of host antiviral innate immune responses by HSV-1.
HSV-1, a virus with linear double-stranded DNA, is recognized by cytosolic DNA sensors when infecting cells. Among these DNA sensors, cyclic GMP-AMP synthase (cGAS), which is a nucleotidyltransferase, is demonstrated to be the predominant cytosolic DNA sensor. Upon binding to DNA fragments, cGAS utilizes GTP and ATP to produce cyclic-GMP-AMP (cGAMP) through its enzymatic activity and cGAMP activates endoplasmic reticulum (ER)-resident receptor, stimulator of interferon gene (STING). Activated STING then recruits TANK-binding kinase 1 (TBK1) and traffics from ER to a perinuclear endosomal compartment, leading to the activation of transcription factors NF-κB and IFN regulatory factors 3 (IRF3), which induce IFN-β production. The signaling is critical for inhibiting HSV-1 replication. In this study, UL36USP was shown to inhibit IFN stimulatory DNA (ISD) or cGAS-STING induced IFN-β and NF-κB activation. UL36USP restricted NF-κB activation mediated by overexpression of STING, TBK1 and IκB kinase, but not p65. Furthermore, UL36USP was demonstrated to deubiquitinate IκBα and restrict its degradation, and finally abrogate NF-κB activation in conditions of HSV-1 infection. More importantly, the recombinant HSV-1 lacking UL36USP DUB activity, denoted as C40A mutant HSV-1, failed to cleave polyubiquitin chains on IκBα. In summary, these findings expand our understanding upon the mechanisms utilized by HSV-1 to evade the host antiviral innate immune defense.
Ms. Ruijie Ye and Ms. Chenhe Su are the co-first authors and Ms. Haiyan Xu is a contributing author. Prof. Chunfu Zheng is the corresponding author. Work in the Zheng laboratory relevant to this article was supported by grants from the National Natural Science Foundation of China (81371795 and 81571974).