Kaposi’s Sarcoma Associated Herpesvirus Encoded Viral FLICE Inhibitory Protein K13 Activates NF-κB Pathway Independent of TRAF6, TAK1 and LUBACReport as inadecuate




Kaposi’s Sarcoma Associated Herpesvirus Encoded Viral FLICE Inhibitory Protein K13 Activates NF-κB Pathway Independent of TRAF6, TAK1 and LUBAC - Download this document for free, or read online. Document in PDF available to download.

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 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-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.



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

Source: http://plos.srce.hr/



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