Cells with a normal version of HPK1 (left) carry fewer microclusters (green spots) than does a cell with a faulty version of HPK1 (right).

Cells with a normal version of HPK1 (left) carry fewer microclusters (green spots) than does a cell with a faulty version of HPK1 (right).

Like a fire alarm that keeps ringing after the blaze is out, the T cell receptor (TCR) can cause problems if it continues transmitting signals. Lasserre et al. clarify the intricate mechanism that turns off the receptor.

The TCR detects pathogens and enlists the adaptive immune system to combat the invaders. On the surface of a T cell, TCR molecules huddle with several other kinds of proteins to form signaling microclusters. However, prolonged signaling can prompt autoimmune attacks, so cells need a way to disperse the microclusters. Previous work suggested that the protein kinase HPK1 inhibits T cell signaling by phosphorylating a key microcluster adaptor called SLP76, spurring it to bind to members of the 14-3-3 protein family. But how HPK1's actions turned down TCR signaling remained unclear.

Lasserre et al. showed that HPK1 slips into microclusters and breaks them up. To join a microcluster, SLP76 first hooks up with the protein GADS, which connects to another protein, LAT, that admits the pair to the microcluster. HPK1 phosphorylated not only SLP76 but also GADS, prompting both molecules to link up with 14-3-3 proteins. In turn, the 14-3-3 proteins force SLP76 and GADS to separate from LAT, breaking up the microcluster and curbing signaling. In the future, researchers will need to work out the mechanism that adjusts HPK1 activity under normal and pathological conditions. Mice and humans lacking the protein are prone to autoimmune diseases, suggesting that it may be a promising target for drugs to treat these illnesses.

References

References
Lasserre
R.
et al
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2011
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J. Cell Biol.
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