Journal article
The PP4R1 subunit of protein phosphatase PP4 targets TRAF2 and TRAF6 to mediate inhibition of NF-κB activation
Cellular signalling, Vol.26(12), pp.2730-2737
12/2014
DOI: 10.1016/j.cellsig.2014.08.001
PMID: 25134449
Abstract
TRAFs constitute a family of proteins that have been implicated in signal transduction by immunomodulatory cellular receptors and viral proteins. TRAF2 and TRAF6 have an E3-ubiquitin ligase activity, which is dependent on the integrity of their RING finger domain and it has been associated with their ability to activate the NF-κB and AP1 signaling pathways. A yeast two-hybrid screen with TRAF2 as bait, identified the regulatory subunit PP4R1 of protein phosphatase PP4 as a TRAF2-interacting protein. The interaction of TRAF2 with PP4R1 depended on the integrity of the RING finger domain of TRAF2. PP4R1 could interact also with the TRAF2-related factor TRAF6 in a RING domain-dependent manner. Exogenous expression of PP4R1 inhibited NF-κB activation by TRAF2, TRAF6, TNF and the Epstein–Barr virus oncoprotein LMP1. In addition, expression of PP4R1 downregulated IL8 induction by LMP1, whereas downregulation of PP4R1 by RNA interference enhanced the induction of IL8 by LMP1 and TNF. PP4R1 could mediate the dephosphorylation of TRAF2 Ser11, which has been previously implicated in TRAF2-mediated activation of NF-κB. Finally, PP4R1 could inhibit TRAF6 polyubiquitination, suggesting an interference with the E3 ubiquitin ligase activity of TRAF6. Taken together, our data identify a novel mechanism of NF-κB pathway inhibition which is mediated by PP4R1-dependent targeting of specific TRAF molecules.
•PP4R1 can interact with TRAF2 and TRAF6 in a RING-domain-dependent manner•PP4R1 can inhibit NFκB activation by TRAF2, TRAF6, TNF and the EBV oncoprotein LMP1•PP4R1 can mediate the dephosphorylation of TRAF2 Ser11•PP4R1 can affect negativelyTRAF6 polyubiquitination
Details
- Title: Subtitle
- The PP4R1 subunit of protein phosphatase PP4 targets TRAF2 and TRAF6 to mediate inhibition of NF-κB activation
- Creators
- Paul Hadweh - School of Biology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Macedonia, GreeceHasem Habelhah - Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United StatesElliott Kieff - Department of Medicine and Microbiology and Molecular Genetics, Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United StatesGeorge Mosialos - School of Biology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Macedonia, GreeceEudoxia Hatzivassiliou - Laboratory of Biological Chemistry, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Macedonia, Greece
- Resource Type
- Journal article
- Publication Details
- Cellular signalling, Vol.26(12), pp.2730-2737
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.cellsig.2014.08.001
- PMID
- 25134449
- ISSN
- 0898-6568
- eISSN
- 1873-3913
- Grant note
- name: European Union Sixth Research Framework Programme, award: LSHC-CT-2005-018704; DOI: 10.13039/501100002752, name: Bodossaki Foundation, award: reference number 1042/665/epsilonk; DOI: 10.13039/100002854, name: ESF; name: National Strategic Reference Framework, award: proposal code number 303
- Language
- English
- Date published
- 12/2014
- Academic Unit
- Pathology
- Record Identifier
- 9984047722502771
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