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Kaposi’s Sarcoma Associated Herpesvirus Encoded Viral FLICE Inhibitory Protein K13 Activates NF-?B Pathway Independent of TRAF6, TAK1 and LUBAC
Published: Tuesday, May 08, 2012
Author: Hittu Matta et al.

by Hittu Matta, Ramakrishnan Gopalakrishnan, Ciaren Graham, Bhairavi Tolani, Akshat Khanna, Han Yi, Yulan Suo, Preet M. Chaudhary


Kaposi’s sarcoma associated herpesvirus encoded viral FLICE inhibitory protein (vFLIP) K13 activates the NF-?B pathway by binding to the NEMO/IKK? subunit of the I?B 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-?B 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 (Sharpincpdm/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-?B activity. K13-induced NF-?B 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/IKKa and IKK2/IKKß, which resulted in their activation by “T Loop” phosphorylation.


Our results demonstrate that K13 activates the NF-?B pathway by binding to NEMO which results in the recruitment of IKK1/IKKa and IKK2/IKKß and their subsequent activation by phosphorylation. Thus, K13 activates NF-?B 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-?B for the treatment of KSHV-associated malignancies.