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PARL mediates Smac proteolytic maturation in mitochondria to promote apoptosis

Shotaro Saita1, Hendrik Nolte1, Kai Uwe Fiedler1

  • 1Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne 50931, Germany.

Nature Cell Biology
|March 14, 2017
PubMed

Insights

The rhomboid protease PARL processes the pro-apoptotic protein Smac (DIABLO), crucial for caspase activation during apoptosis. PARL

Area of Science:

  • Mitochondrial biology
  • Cell death pathways
  • Protease function

Background:

  • Mitochondria release proteins to trigger apoptosis.
  • PARL is an inner membrane protease with unclear roles in apoptosis.
  • Smac (DIABLO) promotes apoptosis by inhibiting IAPs.

Purpose of the Study:

  • To define the substrate spectrum of PARL.
  • To elucidate PARL's role in apoptosis regulation.

Main Methods:

  • PARL-based proteomics to identify substrates.
  • Analysis of Smac processing and function in PARL-deficient cells.
  • Functional rescue experiments using Smac peptidomimetics and XIAP downregulation.

Main Results:

  • Smac (DIABLO) was identified as a PARL substrate.
  • PARL cleavage generates the IAP-binding motif on Smac, essential for its apoptotic activity.
  • Loss of PARL impairs Smac maturation, preventing XIAP binding and apoptosis.
  • PARL-mediated Smac processing is an independent pro-apoptotic pathway from OPA1-dependent cristae remodeling.

Conclusions:

  • PARL possesses a pro-apoptotic function.
  • PARL-mediated Smac processing is critical for initiating apoptosis.
  • Mitochondrial apoptosis involves distinct pathways regulated by PARL and OPA1.

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