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Study finds key protein for firing up central nervous system inflammation
Date:5/2/2013

al infections are a known environmental trigger for the onset and maintenance of multiple sclerosis and the induction of EAE in mice. Toll-like receptors that detect pathogens play a roll in MS and EAE. They were suspected of involvement in microglial activation and inflammation.

Upon sensing microbes or cell damage, toll-like receptors launch a signaling cascade that activates a variety of genes involved in inflammation and white blood cell homing to the microbes or injury site.

Peli1 is known as a targeting agent, marking proteins with molecules called ubiquitins, ensuring they are functionally modified or found by cellular protein-destruction machinery. In this case, Sun and colleagues found that Peli1 ubiquitinates another targeting agent as a signal, which in turn marks a crucial anti-inflammatory protein for destruction.

The team found:

  • Mice with Peli1 knocked out were resistant to EAE. Those with Peli1 developed severe symptoms including a gradual increase in paralysis.
  • Mice with intact Peli1 had high levels of microglial activation after EAE began and low levels of resting microglia. Mice with Peli1 knocked out had high levels of resting microglia.
  • Expression of proinflammatory chemokines and cytokines was impaired in microglia taken from Peli1 knockout mice. Peli1 sends signal to destroy Traf3

Sun and colleagues then tracked down the role Peli1 plays in protecting one of the molecular networks that is set off when toll-like receptors detect microbes or injury. The MAPK pathway activates a variety of genes involved in inflammation and T cell response.

MAPK is kept in check by a protein called Traf3. The team found that Peli1 signals another ubiquitin ligase that in turn marks Traf3 for destruction, liberating the MAPK network.

After EAE is induced, mice with intact Peli1 have a gradual depletion of Traf3 in their microglia. Traf3 accumulated in the microglia of Pe
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Contact: Scott Merville
smerville@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert

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