title: Kaposi's sarcoma-associated herpesvirus-encoded latency-associated nuclear antigen reduces interleukin-8 expression in endothelial cells and impairs neutrophil chemotaxis by degrading nuclear p65.
abstract: Latency-associated nuclear antigen 1 (LANA-1) of Kaposi's sarcoma-associated herpesvirus (KSHV) is the major viral latent protein and functions as a multifaceted protein. Here, we report that LANA-1 attenuates the endothelial response to tumor necrosis factor alpha (TNF-α) stimulation and inhibits consequent neutrophil chemotaxis. Reporter assays showed that LANA-1 constantly repressed nuclear factor (NF)-κB transactivity upon TNF-α stimulation. We also found that LANA-1 decreased nuclear p65 protein levels through enhancement of polyubiquitylation-mediated p65 degradation and that an elongin B/elongin C-cullin 5-LANA-1-p65 complex assembled by LANA-1 was responsible for this enhanced p65 degradation. In telomerase-immortalized human umbilical vein endothelial cells, LANA-1 was demonstrated to repress interleukin-8 expression, which was involved in neutrophil recruitment to the inflammatory site. Through an in vitro transmigration assay, we determined a suppressive effect of LANA-1 on neutrophil chemotaxis. Our work suggests that KSHV LANA-1 is a negative modulator of acute inflammation and sheds light on a new mechanism by which KSHV during the latent life cycle evades the host innate immune response.
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, 225 South Chongqing Road, Shanghai 200025, People's Republic of China.
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Li
authors.forename: Deguang
authors.initials: D
authors.lastname: Liang
authors.forename: Xianzhi
authors.initials: X
authors.lastname: Lin
authors.forename: Erle S
authors.initials: ES
authors.lastname: Robertson
authors.forename: Ke
authors.initials: K
authors.lastname: Lan
mesh_terms: D000956:Antigens, Viral / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D054441:Cell Migration Assays, Leukocyte; D002465:Cell Movement; D042783:Endothelial Cells / Q000821:virology*; D017930:Genes, Reporter; D019288:Herpesvirus 8, Human / Q000276:immunology / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D016209:Interleukin-8 / Q000037:antagonists & inhibitors*; D009504:Neutrophils / Q000276:immunology*; D009687:Nuclear Proteins / Q000276:immunology / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D000956:Antigens, Viral; C508606:CXCL8 protein, human; D016209:Interleukin-8; D009687:Nuclear Proteins; C498143:RELA protein, human; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C109540:latency-associated nuclear antigen