Matta, M., Gopalakrishnan, R., Graham, Ciaren , Tolani, B., Khanna, A., Yi, H., Suo, Y. and Chaudhary, P. M. (2012) Kaposi's sarcoma associated herpesvirus encoded viral FLICE inhibitory protein K13 activates NF-κB pathway independent of TRAF6, TAK1 and LUBAC. PloS One, 7 (5). e36601. ISSN 1932-6203
Full content URL: http://dx.doi.org/10.1371/journal.pone.0036601
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Item Type: | Article |
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Item Status: | Live Archive |
Abstract
BACKGROUND:
Kaposi's sarcoma associated herpesvirus encoded viral FLICE inhibitory protein (vFLIP) K13 activates the NF-κB pathway by binding to the NEMO/IKKγ subunit of the IκB kinase (IKK) complex. However, it has remained enigmatic how K13-NEMO interaction results in the activation of the IKK complex. Recent studies have implicated TRAF6, TAK1 and linear ubiquitin chains assembled by a linear ubiquitin chain assembly complex (LUBAC) consisting of HOIL-1, HOIP and SHARPIN in IKK activation by proinflammatory cytokines.
METHODOLOGY/PRINCIPAL FINDINGS:
Here we demonstrate that K13-induced NF-κB DNA binding and transcriptional activities are not impaired in cells derived from mice with targeted disruption of TRAF6, TAK1 and HOIL-1 genes and in cells derived from mice with chronic proliferative dermatitis (cpdm), which have mutation in the Sharpin gene (Sharpin(cpdm/cpdm)). Furthermore, reconstitution of NEMO-deficient murine embryonic fibroblast cells with NEMO mutants that are incapable of binding to linear ubiquitin chains supported K13-induced NF-κB activity. K13-induced NF-κB activity was not blocked by CYLD, a deubiquitylating enzyme that can cleave linear and Lys63-linked ubiquitin chains. On the other hand, NEMO was required for interaction of K13 with IKK1/IKKα and IKK2/IKKβ, which resulted in their activation by "T Loop" phosphorylation.
CONCLUSIONS/SIGNIFICANCE:
Our results demonstrate that K13 activates the NF-κB pathway by binding to NEMO which results in the recruitment of IKK1/IKKα and IKK2/IKKβ and their subsequent activation by phosphorylation. Thus, K13 activates NF-κB via a mechanism distinct from that utilized by inflammatory cytokines. These results have important implications for the development of therapeutic agents targeting K13-induced NF-κB for the treatment of KSHV-associated malignancies.
Keywords: | KSHV, K13, NEMO, TRAF, Inflammation, Ubiquitin |
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Subjects: | C Biological Sciences > C540 Virology C Biological Sciences > C700 Molecular Biology, Biophysics and Biochemistry |
Divisions: | College of Science > School of Life Sciences |
ID Code: | 7320 |
Deposited On: | 21 Jan 2013 12:40 |
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