A new mouse model promises to provide some insights into the physiological function of pyrin, an intracellular protein, and its role in familial Mediterranean fever.
Identifying the gene behind an inherited disorder is always a triumphant moment, but this is when the real challenge — understanding how the gene causes disease — begins. Six years ago, familial Mediterranean fever (FMF), a recessive genetic disorder that is characterized by recurrent inflammation and fever, was shown to be caused by mutations in a gene encoding a new protein now known as pyrin. But the physiological function of pyrin and its role in FMF has not yet been resolved. Now, a new mouse model, reported in Molecular Cell, promises to provide some clarity.
Pyrin is an intracellular protein that contains a new protein–protein interaction module known as the pyrin domain (PYD), which has now been found in several molecules that regulate apoptosis and inflammation. One of these is the adaptor protein ASC (apoptosis-associated speck-like protein with a CARD), which can interact with pyrin through a PYD–PYD homotypic association. ASC is known to trigger autocatalysis of caspase-1, which cleaves the pro-inflammatory cytokine interleukin-1 (IL-1) into its active form. On the basis of these observations, it was proposed that pyrin might control the production of IL-1 through ASC and that this regulation is disrupted in individuals with FMF. But in vivo evidence in support of this mechanism has been lacking.
To get a clearer picture of the physiological role of pyrin, Jae Jin Chae and colleagues generated mice that expressed a carboxy-terminal truncated form of pyrin that contains an intact PYD, similar to the mutant protein in FMF. These mice experienced episodes of fever and were hyper-responsive to lipopolysaccharide (LPS). LPS-induced IL-1 processing and caspase-1 activity was markedly increased in pyrin-mutant macrophages compared with controls, which supports the idea that pyrin regulates IL-1 processing. Retroviral transduction of macrophage cell lines with full-length pyrin completely inhibited IL-1 processing, providing further support for this hypothesis.
But this might not be the whole story. The pyrin-mutant macrophages also seemed to be less susceptible to apoptosis and this resistance was independent of IL-1. As defective apoptosis has been associated with other inflammatory disorders, this could potentially be another mechanism that contributes to FMF.
Jennifer Bell
References
Chae, J. J. et al. Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to endotoxin and a defect in macrophage apoptosis. Mol. Cell11, 591–604 (2003). | PubMed |
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