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Survivin does not influence the anti-apoptotic action of XIAP on caspase-9

Franziska K Zumbrägel1, Dominik A Machtens1, Ute Curth1

  • 1Hannover Medical School, Institute for Biophysical Chemistry, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.

Biochemical and Biophysical Research Communications
|November 21, 2016
PubMed

Insights

Survivin does not directly inhibit caspase-9 or interact with XIAP, challenging its proposed role in apoptosis regulation. This study revises the understanding of survivin

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • Survivin is a protein that inhibits apoptosis and is a target for cancer therapy.
  • Its anti-apoptotic effect is thought to involve direct interaction with XIAP (X-linked inhibitor of apoptosis) and antagonism of Smac.
  • This interaction is believed to synergistically inhibit caspase-9 and stabilize XIAP by reducing auto-ubiquitination.

Purpose of the Study:

  • To investigate the influence of survivin on XIAP-mediated inhibition of caspase-9 in vitro.
  • To determine if survivin physically interacts with XIAP.
  • To assess survivin's effect on XIAP auto-ubiquitination.

Main Methods:

  • Fluorescence-based assay for caspase-9 activity.
  • Analytical size exclusion chromatography (SEC).
  • Analytical ultracentrifugation.
  • In vitro XIAP auto-ubiquitination assay.

Main Results:

  • Survivin did not affect XIAP's inhibition of caspase-9, with or without Smac.
  • Survivin does not physically interact with XIAP.
  • Survivin did not influence the kinetics or extent of XIAP self-ubiquitination.

Conclusions:

  • The findings challenge the established model of survivin's direct interaction with XIAP.
  • Survivin's role in regulating the mitochondrial apoptosis pathway may not involve direct inhibition of caspase-9 or interaction with XIAP.
  • Results necessitate a revision of how survivin interferes with apoptosis.
Keywords:
ApoptosisCaspase inhibitionSmacSurvivinUbiquitinationXIAP

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