TRAF2 Controls Death Receptor-Induced Caspase-8 Processing and Facilitates Proinflammatory Signaling

Abstract

Tumor necrosis factor (TNF) receptor associated factor-2 (TRAF2) knockout (KO) cells were generated to investigate the role of TRAF2 in signaling by TNFR1 and the CD95-type death receptors (DRs) 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 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 argue for (i) a non-obligate promoting function of TRAF2 in proinflammatory DR signaling and (ii) a yet unrecognized stabilizing effect of TRAF2 on caspase-8 activity.

Identification, Characterization, and Transcriptional Reprogramming of Epithelial Stem Cells and Intestinal Enteroids in Simian Immunodeficiency Virus Infected Rhesus Macaques

“…In a previous study, we detected iEC apoptosis and the loss of ZO-1 expression during acute and chronic SIV infection in the small intestine (7). Downregulation of apoptosis inhibitor DEGs like XIAP, IKBKB, AKT2, TRAF2, NFKBIA, BIRC2, and BCL2L1 in this study is suggestive of an impaired apoptosis regulatory mechanism in enteroids from chronically SIVinfected RhMs (62,63). Upregulation of the ENDOG gene, which can modulate the caspase-independent apoptotic pathway after cleaving nucleic acids (64), was detected in enteroids from SIV-infected RhMs.…”

cIAP1/TRAF2 interplay promotes tumor growth through the activation of STAT3

“…We checked that these mutants lost their ability to binding is required for cIAP1 to stimulate tumor growth. It is worth noting that we were unable to obtain TRAF2 depleted MEFs (either by guide-RNA genome editing or shRNA), suggesting that the deletion of TRAF2 caused cell death as already reported (15).…”

Comparative Transcriptome Analysis of the Regenerating Zebrafish Telencephalon Unravels a Resource With Key Pathways During Two Early Stages and Activation of Wnt/β-Catenin Signaling at the Early Wound Healing Stage

“…Apoptosis is also activated in the early regenerative phase of various tissues including Xenopus tail, mouse liver, and cornea and is indispensable for effective wound healing ( Tseng et al, 2007 ; Wilson et al, 2007 ; Li et al, 2010 ). Remarkably, we observed a significant upregulation of the apoptosis-related genes including apaf1 , baxa , traf4b , tgfb2 , sgk1 , and casp3a selectively in the lesioned hemisphere at 20 hpl ( Elmore, 2007 ; Gilbert et al, 2016 ; Liu et al, 2017 ; Kreckel et al, 2019 ). Strikingly, many of them were downregulated when Wnt/β-catenin signaling was suppressed, pointing out a positive regulatory role for Wnt signaling in apoptosis during early brain regeneration.…”