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Enhanced cytoprotective effects of the inhibitor of apoptosis protein cellular IAP1 through stabilization with TRAF2

Rebecca A Csomos1, Graham F Brady, Colin S Duckett

  • 1Departments of Pathology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.

The Journal of Biological Chemistry
|June 10, 2009
PubMed

Insights

Cellular IAP (c-IAP) proteins are unstable and undergo autoubiquitination. TNF receptor-associated factor 2 (TRAF2) stabilizes c-IAP1, preventing cell death by sequestering Smac/DIABLO.

Area of Science:

  • Cellular signaling pathways
  • Apoptosis regulation
  • Protein ubiquitination

Background:

  • Inhibitor of apoptosis (IAP) proteins regulate cell death.
  • X-linked IAP inhibits caspases, but cellular IAPs (c-IAPs) do not.
  • Mechanisms of c-IAP-mediated cell survival are unclear.

Purpose of the Study:

  • To elucidate the mechanism of cytoprotection by c-IAP proteins.
  • To investigate the role of TNF receptor-associated factor 2 (TRAF2) in c-IAP stability.
  • To understand how c-IAPs influence the apoptotic threshold.

Main Methods:

  • Investigated c-IAP protein stability and autoubiquitination.
  • Examined the effect of TRAF2 coexpression on c-IAP1 ubiquitination.
  • Assessed the impact of TRAF2 deficiency on c-IAP1 levels.
  • Studied the interaction of stabilized c-IAP1 with Smac/DIABLO.

Main Results:

  • c-IAPs are inherently unstable and undergo autoubiquitination.
  • TRAF2 inhibits c-IAP1 autoubiquitination by blocking its E3 ubiquitin ligase activity.
  • Loss of TRAF2 leads to reduced c-IAP1 levels.
  • Stabilized c-IAP1 sequesters Smac/DIABLO, preventing antagonism of X-linked IAP and promoting cell survival.

Conclusions:

  • c-IAP1 utilizes an autoubiquitination-dependent mechanism for cytoprotection.
  • TRAF2 stabilizes c-IAP1, thereby modulating apoptosis.
  • This study provides insight into IAP protein function in regulating cell death.

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