Scientists Create Map For Doomsday Pathway In Cells

SOPHIA LI
JANUARY 31, 2012

In the latest issue of the journal Cell, Chinese researchers unravel important steps of the necrosis pathway previously unknown to researchers.

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AsianScientist (Jan. 31, 2012) – In the latest issue of the journal Cell, a research team led by Xiaodong Wang of the National Institute of Biological Sciences (NIBS) has unraveled important steps of a cell death pathway previously unknown to researchers.

Cell death – responsible for the separation of our finger digits from a webbed state and other life processes – can only be executed with complicated and tight regulation. Cells destined for death that escape their “doomsday” fate become immortalized, leading to unwanted consequences such as tumor formation and cancer.

Two major forms of programmed cell death exist: apoptosis and necrosis. In apoptosis, the pathway involving proteins of the caspase family is well-characterized; in necrosis, however, many components of the pathway remain unclear.

In the first paper, lead author Sun and colleagues performed a screen that led to the discovery a small molecule inhibitor, necrosulfonamide, which could inhibit necrosis from taking place. The chemical did not block the interaction between receptor-interacting serine-threonine kinase 3 (RIP3) and RIP1, which forms a complex called the necrosome, but instead inhibited one or more unknown downstream steps.

By using mass spectrometry and other biochemical techniques, the team discovered that the inhibitor interacted with a protein called mixed lineage kinase-domain like protein (MLKL). Treating cells with necrosulfonamide or knocking down MLKL expression arrested necrosis at a specific step at which RIP3 formed discrete punctae in cells, suggesting that MLKL is an important adaptor protein in transducing signals from RIP3 to its downstream targets.

In the second paper, lead author Wang and colleagues discovered that a mitochondrial protein phosphatase PGAM5 acted as an antenna, converging multiple necrosis pathways into one.

Knocking down either splice variant of PGAM5 – PGAM5L (long form) or PGAM5S (short form) – attenuated necrosis caused by various signals, whereas knocking down RIP3 and MLKL blocked only TNF-α-mediated necrosis.

By piecing together the biochemical pathways of necrosis, these two studies not only contribute to an understanding of the downstream steps of necrosis, but also challenge conventional notion that necrosis is an unregulated and haphazard way for a cell to die.

The articles can be found at:

• Sun L et al. (2012) Mixed Lineage Kinase Domain-like Protein Mediates Necrosis Signaling Downstream of RIP3 Kinase.
• Wang Z et al. (2012) The Mitochondrial Phosphatase PGAM5 Functions at the Convergence Point of Multiple Necrotic Death Pathways.

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Copyright: Asian Scientist Magazine.
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