A role for Nod-like receptors in autophagy induced byShigellainfection

Shigella infection, the cause of bacillary dysentery, induces caspase-1 activation and cell death in macrophages, but the precise mechanisms remain poorly understood. In our recent study, we presented evidence that caspase-1 activation and IL-1β processing induced by Shigella are mediated through Ipaf, a cytosolic pattern-recognition receptor of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family and the adaptor protein apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC). We also show that Ipaf and caspase-1 were critical for pyroptosis, a specialized form of caspase-1-dependent cell death induced in macrophages by bacterial infection, whereas ASC is dispensable. Notably, infection of macrophages with Shigella induced autophagy, which was dramatically increased by the absence of caspase-1 or Ipaf, but not ASC. Furthermore, autophagy induction was associated with transient resistance to pyroptosis. These results indicate that autophagy in macrophages is regulated by the Ipaf inflammasome, providing a novel function for NLR proteins in bacterial-host interactions.Addendum to: Suzuki T, Franchi L, Toma C, Ashida H, Ogawa M, Yoshikawa Y, Mimuro H, Inohara N, Sasakawa C, Núñez G. Differential regulation of caspase-1 activation, pyroptosis and autophagy via Ipaf and ASC in Shigella-infected macrophages. PLoS Pathog 2007; 3:e111