title: The Itch ubiquitin ligase is required for KSHV RTA induced vFLIP degradation.
abstract: Expression of Kaposi's sarcoma herpesvirus vFLIP, a potent activator of NFkB signaling, promotes latency. Inhibition of NFkB signaling promotes lytic reactivation. We previously reported that lytic inducer, RTA, inhibits vFLIP induced NFkB signaling by inducing the degradation of vFLIP via the proteasome. Here we report that the cellular ubiquitin ligase, Itch, is required for RTA induced degradation of vFLIP. Expression of either Itch targeting shRNA or a dominant negative mutant of the ubiquitin ligase both increased the stability of vFLIP in the presence of RTA. Itch potently ubiquitinated vFLIP in vivo and in vitro. We provide evidence for interaction between RTA, vFLIP and Itch and we identified an RTA resistant mutant of vFLIP that is unable to interact with Itch. These observations contribute to our understanding of how RTA counteracts the activities of vFLIP.
authors.affiliation: Department of Biological Sciences, Towson University, 8000 York Rd, Towson, MD 21252, USA.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Chmura
authors.affiliation: Department of Biological Sciences, Towson University, 8000 York Rd, Towson, MD 21252, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Herold
authors.affiliation: Department of Biological Sciences, Towson University, 8000 York Rd, Towson, MD 21252, USA.
authors.forename: Ayana
authors.initials: A
authors.lastname: Ruffin
authors.affiliation: Department of Biological Sciences, Towson University, 8000 York Rd, Towson, MD 21252, USA.
authors.forename: Trudymae
authors.initials: T
authors.lastname: Atuobi
authors.affiliation: Department of Biological Sciences, Towson University, 8000 York Rd, Towson, MD 21252, USA.
authors.forename: Yetunde
authors.initials: Y
authors.lastname: Fabiyi
authors.affiliation: Department of Biological Sciences, Towson University, 8000 York Rd, Towson, MD 21252, USA.
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Mitchell
authors.affiliation: Viral Oncology Program, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1, Baltimore, MD 21231, USA.
authors.forename: Young Bong
authors.initials: YB
authors.lastname: Choi
authors.affiliation: Department of Biological Sciences, Towson University, 8000 York Rd, Towson, MD 21252, USA. Electronic address: eehrlich@towson.edu.
authors.forename: Elana S
authors.initials: ES
authors.lastname: Ehrlich
mesh_terms: D006566:Herpesviridae Infections / Q000201:enzymology* / Q000235:genetics / Q000821:virology; D019288:Herpesvirus 8, Human / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D059748:Proteolysis; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D017874:Immediate-Early Proteins; D012097:Repressor Proteins; C417604:Rta protein, Human herpesvirus 8; D015534:Trans-Activators; D014764:Viral Proteins; C481275:viral FLIP protein, Human herpesvirus 8; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases
keywords: AIP4; HHV-8; Herpesvirus; Itch; KSHV; Kaposi's sarcoma; NF-κB; RTA; Ubiquitin; vFLIP