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TRAF3 and NBR1 both influence the effect of the disease-causing CYLD(Arg936X) mutation on NF-κB activity

Lookup NU author(s): Professor Neil RajanORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2021 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.Recently described Hungarian and Anglo-Saxon pedigrees that are affected by CYLD cutaneous syndrome (syn: Brooke-Spiegler syndrome (BSS)) carry the same disease-causing mutation (c.2806C>T, p.Arg936X) of the cylindromatosis (CYLD) gene but exhibit striking phenotypic differences. Using whole exome sequencing, missense genetic variants of the TRAF3 and NBR1 genes were identified in the affected family members of the Hungarian pedigree that are not present in the Anglo-Saxon pedigree. This suggested that the affected proteins (TRAF3 and NBR1) are putative phenotype-modifying factors. An in vitro experimental system was set up to clarify how wild type and mutant TRAF3 and NBR1 modify the effect of CYLD on the NF-κB signal transduction pathway. Our study revealed that the combined expression of mutant CYLD(Arg936X) with TRAF3 and NBR1 caused increased NF-κB activity, regardless of the presence or absence of mutations in TRAF3 and NBR1. We concluded that increased expression levels of these proteins further strengthen the effect of the CYLD(Arg936X) mutation on NF-κB activity in HEK293 cells and may explain the phenotype-modifying effect of these genes in CYLD cutaneous syndrome. These results raise the potential that detecting the levels of TRAF3 and NBR1 might help explaining phenotypic differences and prognosis of CCS.

Publication metadata

Author(s): Danis J, Kelemen E, Rajan N, Nagy N, Szell M, Adam E

Publication type: Article

Publication status: Published

Journal: Experimental Dermatology

Year: 2021

Volume: 30

Issue: 11

Pages: 1705-1710

Print publication date: 01/11/2021

Online publication date: 17/05/2021

Acceptance date: 26/04/2021

Date deposited: 01/11/2023

ISSN (print): 0906-6705

ISSN (electronic): 1600-0625

Publisher: Blackwell Publishing Ltd


DOI: 10.1111/exd.14365


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Funder referenceFunder name
Bolyai János Research Fellowship
EU’s Horizon 2020 Research and Innovation Program 739593
Hungarian Research Development and Innovation Office EFOP-3.6.1-16-2016-00008, GINOP-2.3.2-15-2016-00039, OTKA K128736
New National Excellence Program of the Hungarian Ministry for Innovation and Technology ÚNKP-20-3, ÚNKP-20-5