The N-terminus of PKR is responsible for the activation of the NF-kappaB signaling pathway by interacting with the IKK complex

Bonnet, Marion ORCID: https://orcid.org/0000-0002-7559-2413, Daurat, Caroline, Ottone, Catherine and Meurs, Eliane F. 2006. The N-terminus of PKR is responsible for the activation of the NF-kappaB signaling pathway by interacting with the IKK complex. Cellular Signalling 18 (11) , pp. 1865-1875. 10.1016/j.cellsig.2006.02.010

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Abstract

The interferon-induced double-stranded RNA (dsRNA)-activated protein kinase (PKR) has been shown to activate NF-κB independently of its kinase function after interaction with the IKK complex. In order to investigate the mechanism of NF-κB activation by PKR, we identified the domain of PKR responsible for stimulating the NF-κB pathway in PKR-deficient fibroblasts using an NF-κB dependent reporter assay. The N-terminal 1–265 AA of PKR activates NF-κB, whereas the 1–180 AA N-terminus restricted to the two dsRNA Binding Domains (DRBD), the third basic domain alone (AA 181–265), or the C-terminus of PKR (AA 266–550) were unable to stimulate the expression of the NF-κB dependent reporter gene. Using confocal microscopy, we confirmed that PKR full length as well as PKR N-terminus colocalized with IKKβ. By GST-pulldown analysis, using different PKR domains, we then revealed the specific ability of the PKR N-terminus 1–265 to bind to and activate IKK and showed that this activation requires the integrity of the IKK complex. This activation is not only due to DRBDs since the DRBD fragment 1–180 failed to inhibit PKR 1–265 induced NF-κB activation. Our results therefore demonstrate that the ability of PKR to mediate NF-κB activation resides in its full N-terminus, and requires both DRBDs and the third basic domain.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Elsevier
ISSN:	0898-6568
Date of First Compliant Deposit:	12 February 2021
Date of Acceptance:	8 February 2006
Last Modified:	09 Nov 2022 10:09
URI:	https://orca.cardiff.ac.uk/id/eprint/138473

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