last updated April 2013
A missing link in antiviral defense
Hints from a rare hereditary disease allow scientists to home in on a key regulator of the immune response to viral infection
The cell surface protein Toll-like receptor 3 (TLR3) is at the vanguard of the antiviral immune response, triggering a potent cascade of inflammatory signals upon detecting viral genetic material.
As a first step in this response, TLR3 undergoes chemical modification by an enzyme that selectively appends phosphate groups to specific amino acids. A team led by Kong-Peng Lam at Singapore’s A*STAR Bioprocessing Technology Institute recently identified this enzyme1, following up on observations that patients suffering from a genetic disease called X-linked agammaglobulinemia (XLA) frequently succumb to infections.
XLA is associated with defects in the gene encoding Bruton’s tyrosine kinase (BTK), and Lam’s group determined that immune cells lacking BTK fail to marshal an adequate response to viral triggers. For example, BTK-deficient macrophages fare worse at fighting dengue virus than their wild-type counterparts. Also, absence of this enzyme generally leads to sharp reductions in the secretion of numerous TLR3-induced immunity-activating signals.
Previous studies have identified a specific tyrosine amino acid that undergoes phosphorylation during TLR3 activation. Lam and colleagues confirmed that BTK is directly responsible for introducing this modification. Mutations that selectively eliminate BTK’s capacity for phosphorylation have the same immunity-impairing effects as BTK deletions, confirming the key role of this protein as a trigger of antiviral response.