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Transnitrosylation of XIAP regulates caspase-dependent neuronal cell death

Tomohiro Nakamura1, Lei Wang, Catherine C L Wong

  • 1Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.

Molecular Cell
|July 31, 2010
PubMed

Insights

Nitric oxide (NO) modifies X-linked inhibitor of apoptosis (XIAP), affecting cell death pathways. This S-nitrosylation of XIAP is implicated in neurodegenerative diseases like Alzheimer's and Parkinson's.

Area of Science:

  • Biochemistry
  • Neuroscience
  • Molecular Biology

Background:

  • X-linked inhibitor of apoptosis (XIAP) inhibits caspases and acts as an E3 ubiquitin ligase.
  • Molecular mechanisms regulating XIAP activity are not fully understood.
  • Nitric oxide (NO) plays a role in neurotoxicity and caspase activation, relevant to neurodegenerative diseases.

Purpose of the Study:

  • To investigate the molecular pathways controlling XIAP activities.
  • To determine the effect of nitric oxide (NO) on XIAP function.
  • To explore the role of XIAP S-nitrosylation in neurodegenerative disorders.

Main Methods:

  • Studied the reaction between nitric oxide (NO) and XIAP.
  • Investigated the formation of S-nitrosylated XIAP (SNO-XIAP).
  • Examined SNO-XIAP levels in post-mortem brain tissues from patients with neurodegenerative diseases.

Main Results:

  • Nitric oxide (NO) S-nitrosylates XIAP's RING domain, forming SNO-XIAP.
  • SNO-XIAP exhibits inhibited E3 ligase and antiapoptotic activity.
  • Significant SNO-XIAP formation was observed in brains of Alzheimer's, Parkinson's, and Huntington's disease patients.
  • Unexpectedly, SNO-caspase can transnitrosylate XIAP, promoting cell injury and death.

Conclusions:

  • Nitric oxide (NO) directly regulates XIAP activity through S-nitrosylation.
  • XIAP S-nitrosylation is implicated in the pathogenesis of neurodegenerative diseases.
  • The interplay between SNO-caspase and XIAP contributes to neuronal damage via nitrosative stress.

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