Abstract
TRAF2 and ASK1 play essential roles in tumor necrosis factor alpha (TNF-alpha)-induced mitogen-activated protein kinase signaling. Stimulation through TNF receptor 2 (TNFR2) leads to TRAF2 ubiquitination and subsequent proteasomal degradation. Here we show that TNFR2 signaling also leads to selective ASK1 ubiquitination and degradation in proteasomes. c-IAP1 was identified as the ubiquitin protein ligase for ASK1 ubiquitination, and studies with primary B cells from c-IAP1 knock-out animals revealed that c-IAP1 is required for TNFR2-induced TRAF2 and ASK1 degradation. Moreover, in the absence of c-IAP1 TNFR2-mediated p38 and JNK activation was prolonged. Thus, the ubiquitin protein ligase activity of c-IAP1 is responsible for regulating the duration of TNF signaling in primary cells expressing TNFR2.
Highlights
Tumor necrosis factor ␣ (TNF),2 a key mediator of the inflammatory response, functions by increasing the expression of a variety of effector molecules such as interleukin-1, interleukin-6, and Interferon-␥ [1]
We show that TNF receptor 2 (TNFR2) signaling leads to selective ASK1 ubiquitination and degradation in proteasomes. c-IAP1 was identified as the ubiquitin protein ligase for ASK1 ubiquitination, and studies with primary B cells from c-IAP1 knock-out animals revealed that c-IAP1 is required for TNFR2-induced TRAF2 and ASK1 degradation
Given that TRAF2 is degraded and TNF-induced JNK is prematurely terminated in TNFR2-expressing Jurkat cells, we asked whether upstream MAPK kinase kinases (MAPKKKs) might be targets of ubiquitination and degradation
Summary
Tumor necrosis factor ␣ (TNF),2 a key mediator of the inflammatory response, functions by increasing the expression of a variety of effector molecules such as interleukin-1, interleukin-6, and Interferon-␥ [1]. The ubiquitin protein ligase activity of c-IAP1 is responsible for regulating the duration of TNF signaling in primary cells expressing TNFR2. C-IAP1, in particular, has been found to play an important role in TNF signaling, being activated by occupancy of TNFR2 and mediating the ubiquitination and subsequent degradation of TRAF2 [17].
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