Human Cytomegalovirus DNA Polymerase Subunit UL44 Antagonizes Antiviral Immune Responses by Suppressing IRF3- and NF-Œ∫B-Mediated Transcription
Authors: Hong-Mei Zou
Yu-Zhi Fu
Shan Su
Yi Guo
Min-Hua Luo
Su-Yun Wang
Shu Li
Yan-Yi Wang
Journal: Journal of Virology (2019)
Discipline: MICROBIOLOGY
Keywords: HCMV; IRF3; NF-Œ∫B; UL44; immune evasion
Affiliations: Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China., Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China., Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China .

Abstract:  Innate immunity is the first line of host defense against viral invasion. The induction of type I interferons (IFNs) and inflammatory cytokines is essential to host antiviral immune responses, which are also key targets of viral immune evasion. Human cytomegalovirus (HCMV) can establish long-term latent infections, in which immune evasion is a pivotal step. In this study, we identified HCMV protein UL44, a DNA polymerase processivity factor, as an inhibitor of the interferon regulatory factor 3 (IRF3)- and NF-Œ∫B-dependent antiviral response. Ectopic expression of UL44 inhibited HCMV-triggered induction of downstream effector genes and enhanced viral replication. Conversely, knockdown of UL44 potentiated HCMV-triggered induction of downstream antiviral genes. UL44 interacted with IRF3 and p65, and it inhibited the binding of IRF3 and NF-Œ∫B to the promoters of their downstream antiviral genes. These findings reveal an important mechanism of immune evasion by HCMV at the transcriptional level.IMPORTANCE Induction of type I IFNs and inflammatory cytokines plays pivotal roles in host antiviral innate immune responses. Viruses have evolved various mechanisms to interfere with these processes. HCMV causes severe ailments in immunodeficient populations and is a major cause of birth defects. It has been shown that HCMV antagonizes host innate immune defenses, which is important for establishing immune evasion and latent infection. In this study, we identified the HCMV DNA polymerase subunit UL44 as a suppressor of antiviral innate immune responses. Overexpression of UL44 impaired HCMV-triggered induction of type I IFNs and other antiviral genes and thus potentiated viral replication, whereas UL44 deficiency showed opposite effects. Mechanistic studies indicated that UL44 acts by inhibiting the binding of IRF3 and NF-Œ∫B to the promoters of downstream antiviral genes. These findings defined an important mechanism of HCMV immune evasion at the transcriptional level, which may provide a therapeutic target for the treatment of HCMV infection. 

Retracted: No

PubPeer comments:
 Lousy author lousy reviewers and editor Totally bullshit paper! Ectopic expression of viral gene during WT HCMV infection might enhance the viral replication a little bit, their results canu2019t be true for enhancing more than 10 folds. It is totally bullshit. If this is for UL44 KO HCMV, ectopic expression of UL44 will significantly enhance viral replication. They have demonstrated the immune evasion roles of other viral proteins, if their result u201cFu201d is true, then the inhibition effect of UL44 should come from other viral proteins as viral replication has increased more than 10 folds, the expression of other immune evasion viral proteins should increase more than 10 folds too.  , 
 Lousy author lousy reviewers and editor Totally bullshit paper! The knockdown effect of UL44RNA#1 is better than that of UL44RNA#2 in Fig. 2A, so the effect of UL44-RNAi to resume the transcription of antiviral genes should be better than that of UL44RNA#2 in Fig 2B.  , 
 Lousy author lousy reviewers and editor Totally bullshit paper! The input is way difference, if the input of TBK1 equals to that of IRF3, they might detect the interaction between UL44 and TBK1.  , 
 The knockdown effect of UL44RNA#1 is better than that of UL44RNA#2 in Fig. 2A, so the effect of UL44-RNAi to resume the transcription of antiviral genes should be better than that of UL44RNA#2 in Fig 2B.  , 
 Ectopic expression of viral gene during WT HCMV infection might enhance the viral replication a little bit, their results canu2019t be true for enhancing more than 10 folds. If this is for UL44 KO HCMV, ectopic expression of UL44 will significantly enhance viral replication. u00a0 They have demonstrated the immune evasion roles of other viral proteins, if their result u201cFu201d is true, then the inhibition effect of UL44 should come from other viral proteins as viral replication has increased more than 10 folds, the expression of other immune evasion viral proteins should increase more than 10 folds too.  , 
 trash data and paper The input is way different, if the input of TBK1 equals to that of IRF3, they might detect the interaction between UL44 and TBK1.  ,