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CRISPR whole-genome screening identifies new necroptosis regulators and RIPK1 alternative splicing

Marinella G Callow1, Colin Watanabe2, Katherine E Wickliffe3

  • 1Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.

Cell Death & Disease
|February 17, 2018
PubMed

Insights

Researchers identified 112 regulators of necroptosis, a cell death pathway involved in disease. They discovered PTBP1, an RNA-binding protein, is crucial for maintaining RIPK1 protein levels, offering new therapeutic targets for necroptosis-related conditions.

Area of Science:

  • Cell Biology
  • Immunology
  • Genetics

Background:

  • Necroptotic cell death is vital for pathogen defense but can cause tissue damage in diseases.
  • The necrosome complex (RIPK1, RIPK3, MLKL) is key, but other regulatory mechanisms are unknown.

Purpose of the Study:

  • To identify novel regulators and mediators of necroptosis.
  • To understand the role of these components in cell death and tissue homeostasis.

Main Methods:

  • CRISPR/Cas9-mediated gene knockout screen in mouse cells.
  • Screening 19,883 protein-coding genes for resistance to cytokine-induced necroptosis.

Main Results:

  • Identified 112 necroptosis regulators, including 59 novel candidates.
  • Discovered PTBP1 regulates RIPK1 protein abundance via alternative splicing.
  • PTBP1's activity is essential for maintaining RIPK1 levels during necroptosis.

Conclusions:

  • The study expands the known components of the necroptosis pathway.
  • PTBP1 emerges as a critical regulator of necroptosis, impacting RIPK1 stability.
  • Findings offer new insights into necroptosis regulation and potential therapeutic strategies.

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