title: The Linear Ubiquitin Assembly Complex Modulates Latent Membrane Protein 1 Activation of NF-κB and Interferon Regulatory Factor 7.
abstract: Recently, linear ubiquitin assembly complex (LUBAC)-mediated linear ubiquitination has come into focus due to its emerging role in activation of NF-κB in different biological contexts. However, the role of LUBAC in LMP1 signaling leading to NF-κB and interferon regulatory factor 7 (IRF7) activation has not been investigated. We show here that RNF31, the key component of LUBAC, interacts with LMP1 and IRF7 in Epstein-Barr virus (EBV)-transformed cells and that LUBAC stimulates linear ubiquitination of NEMO and IRF7. Consequently, LUBAC is required for LMP1 signaling to full activation of NF-κB but inhibits LMP1-stimulated IRF7 transcriptional activity. The protein levels of RNF31 and LMP1 are correlated in EBV-transformed cells. Knockdown of RNF31 in EBV-transformed IB4 cells by RNA interference negatively regulates the expression of the genes downstream of LMP1 signaling and results in a decrease of cell proliferation. These lines of evidence indicate that LUBAC-mediated linear ubiquitination plays crucial roles in regulating LMP1 signaling and functions.
  
  
  
  We show here that LUBAC-mediated linear ubiquitination is required for LMP1 activation of NF-κB but inhibits LMP1-mediated IRF7 activation. Our findings provide novel mechanisms underlying EBV-mediated oncogenesis and may have a broad impact on IRF7-mediated immune responses.
authors.affiliation: Center of Excellence for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA.|Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA.
authors.forename: Yujia
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Center of Excellence for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA.|Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA.
authors.forename: Junping
authors.initials: J
authors.lastname: Ren
authors.affiliation: Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA.
authors.forename: Kenton H
authors.initials: KH
authors.lastname: Hall
authors.affiliation: Center of Excellence for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA.|Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA.|Hepatitis (HCV/HIV) Program, James H. Quillen VA Medical Center, Johnson City, Tennessee, USA.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Moorman
authors.affiliation: Center of Excellence for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA.|Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA.|Hepatitis (HCV/HIV) Program, James H. Quillen VA Medical Center, Johnson City, Tennessee, USA.
authors.forename: Zhi Q
authors.initials: ZQ
authors.lastname: Yao
authors.affiliation: Center of Excellence for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA nings1@etsu.edu.|Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA.
authors.forename: Shunbin
authors.initials: S
authors.lastname: Ning
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D004854:Herpesvirus 4, Human / Q000502:physiology; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism*; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination; D014763:Viral Matrix Proteins / Q000378:metabolism*; D017735:Virus Latency
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; C491731:IKBKG protein, human; D050839:Interferon Regulatory Factor-7; D046912:Multiprotein Complexes; D016328:NF-kappa B; D025801:Ubiquitin; D014763:Viral Matrix Proteins; C558338:RNF31 protein, human; D044767:Ubiquitin-Protein Ligases; D051550:I-kappa B Kinase
keywords: IRF7; LMP1; LUBAC; ubiquitination