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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02024

TRAF2 controls death receptor-induced caspase-8 processing and facilitates proinflammatory signaling

  • 1Department of Internal Medicine II, Division of Molecular Internal Medicine, Universitätsklinikum Würzburg, Germany
  • 2Department of Internal Medicine II, University Hospital of Wuerzburg, Germany

Tumor necrosis factor (TNF) receptor associated factor-2 (TRAF2) knockout cells were generated to investigate the role of TRAF2 in signaling by TNFR1 and the CD95-type death receptors (DR) TRAILR1/2 and CD95. To prevent negative selection effects arising from the increased cell death sensitivity of TRAF2-deficient cells, cell lines were used for the generation of the TRAF2 knockout (KO) variants that were protected from DR-induced apoptosis downstream of caspase-8 activation. As already described in the literature, TRAF2 KO cells displayed enhanced constitutive alternative NFκB signaling and reduced TNFR1-induced activation of the classical NFκB pathway. There was furthermore a significant but only partial reduction in CD95-type DR-induced upregulation of the proinflammatory NFκB-regulated cytokine interleukin-8 (IL8), which could be reversed by reexpression of TRAF2. In contrast, expression of the TRAF2-related TRAF1 protein failed to functionally restore TRAF2 deficiency. TRAF2-deficiency resulted furthermore in enhanced procaspase-8 processing by DRs but this surprisingly came along with a reduction in net caspase-8 activity. In sum our data argues i) for a non-obligate promoting function of TRAF2 in proinflammatory DR signaling and ii) a yet not recognized stabilizing effect of TRAF2 on caspase-8 activity.

Keywords: caspase-8, Death Receptors, CD95, CD95L , TNF, TNFR1 , TRAF1, TRAF2, TRAIL, TRAILR1, TRAILR2

Received: 17 Apr 2019; Accepted: 09 Aug 2019.

Edited by:

Eva Szegezdi, National University of Ireland Galway, Ireland

Reviewed by:

Olivier Micheau, Université de Bourgogne, France
Steven De Jong, University Medical Center Groningen, Netherlands
Myung-Hee Kwon, Ajou University, South Korea  

Copyright: © 2019 Wajant, Kreckel, Anany and Siegmund. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Harald Wajant, Universitätsklinikum Würzburg, Department of Internal Medicine II, Division of Molecular Internal Medicine, Würzburg, 97070, Germany, harald.wajant@uni-wuerzburg.de