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Regulation of a distinct activated RIPK1 intermediate bridging complex I and complex II in TNFα-mediated apoptosis

Palak Amin1, Marcus Florez1, Ayaz Najafov1

  • 1Department of Cell Biology, Harvard Medical School, Boston, MA 02115.

Proceedings of the National Academy of Sciences of the United States of America
|June 13, 2018
PubMed

Insights

We discovered a new cell death pathway called RIPK1-dependent apoptosis (RDA) involving a unique RIPK1 protein complex. NEK1 restricts RDA, while LRRK2 promotes it, offering insights into neurodegenerative diseases.

Area of Science:

  • Cellular biology
  • Molecular mechanisms of cell death
  • Neuroscience

Background:

  • Tumor necrosis factor-alpha (TNFα) triggers multiple cell death pathways.
  • RIPK1-dependent apoptosis (RDA) is poorly understood.
  • Existing knowledge on TNFα-induced cell death needs further elucidation regarding RIPK1's role.

Purpose of the Study:

  • Investigate the molecular mechanisms of RIPK1-dependent apoptosis (RDA).
  • Identify key regulators of RIPK1 activation and iuRIPK1 formation in RDA.
  • Elucidate the role of NEK1 and LRRK2 in TNFα-mediated cell death.

Main Methods:

  • Utilized a targeted siRNA screen of 1,288 genes to identify regulators of iuRIPK1 formation.
  • Analyzed RIPK1 activation, ubiquitination, and complex formation.
  • Investigated the roles of NEK1, LRRK2, APC11, and c-Cbl in cell death pathways.

Main Results:

  • Discovered the formation of a detergent-insoluble, ubiquitinated RIPK1 pool (iuRIPK1) crucial for RDA.
  • NEK1 restricts RDA by inhibiting iuRIPK1 formation, while LRRK2 promotes RIPK1 activation.
  • Identified APC11 and c-Cbl as promoters of RDA, with c-Cbl mediating K63-ubiquitination of RIPK1.
  • Revealed two distinct, differentially regulated modes of TNFα-induced necroptosis involving iuRIPK1.

Conclusions:

  • Uncovered a novel mechanism of RIPK1 activation central to RDA.
  • Demonstrated NEK1's protective role and LRRK2's pro-death role in RDA.
  • Provided new insights into the regulation of cell death pathways relevant to neurodegenerative diseases like ALS and Parkinson's.
Keywords:
RIPK1TNFapoptosisnecroptosisubiquitination

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