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Tumor necrosis factor receptor 2 signaling induces selective c-IAP1-dependent ASK1 ubiquitination and terminates

Yongge Zhao1, Dietrich B Conze, John A Hanover

  • 1Laboratory of Immune Cell Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.

The Journal of Biological Chemistry
|January 16, 2007
PubMed

Insights

Cellular signaling duration is regulated by c-IAP1, a ubiquitin ligase essential for the degradation of TRAF2 and ASK1 proteins. This process controls tumor necrosis factor alpha (TNF-alpha) pathway activation.

Area of Science:

  • Molecular biology
  • Cellular signaling
  • Ubiquitination pathways

Background:

  • Tumor necrosis factor alpha (TNF-alpha) signaling is crucial for cellular responses.
  • TNF receptor 2 (TNFR2) activation triggers TRAF2 ubiquitination and degradation.
  • The precise regulation of ASK1 (Apoptosis Signal-regulating Kinase 1) in this pathway requires further elucidation.

Purpose of the Study:

  • To investigate the role of c-IAP1 in TNFR2-induced signaling.
  • To identify the ubiquitin ligase responsible for ASK1 ubiquitination.
  • To determine how c-IAP1 regulates the duration of TNF signaling.

Main Methods:

  • Utilized primary B cells from c-IAP1 knock-out animals.
  • Investigated protein ubiquitination and degradation.
  • Assessed the activation of downstream kinases like p38 and JNK.

Main Results:

  • Identified c-IAP1 as the ubiquitin ligase for ASK1.
  • Demonstrated that c-IAP1 is essential for TNFR2-induced degradation of both TRAF2 and ASK1.
  • Observed prolonged p38 and JNK activation in the absence of c-IAP1.

Conclusions:

  • c-IAP1's ubiquitin ligase activity is critical for terminating TNFR2 signaling.
  • c-IAP1 regulates the duration of TNF-alpha-induced mitogen-activated protein kinase signaling by controlling protein degradation.
  • This finding highlights c-IAP1 as a key regulator of inflammatory responses mediated by TNFR2.

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