A Caspase for Phagosomal-Lysosomal Fusion

Sci. Signal.  14 Aug 2012:
Vol. 5, Issue 237, pp. ec214
DOI: 10.1126/scisignal.2003495

Inflammasomes are multiprotein complexes consisting of a Nod-like receptor (NLR) protein, an adaptor molecule, and caspase-1. Sensing of microbial products by the NLR stimulates assembly of the inflammasome and activation of caspase-1, which is required for the processing and secretion of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18. In mice, caspase-11 (which is encoded by Casp4) is required for the activation of caspase-1 in response to lipopolysaccharide (LPS) and bacterial toxins. Akhter et al. found that when caspase-11–deficient (Casp4–/–) mouse macrophages were infected with Legionella pneumophilia, which causes Legionnaire’s pneumonia, caspase-1 activation was intact. However, whereas wild-type mouse macrophages eliminated L. pneumophilia, Casp4–/– macrophages failed to do so and the bacteria replicated. Unlike the phagosomes in wild-type cells, in Casp4–/– cells phagosomes containing L. pneumophilia failed to fuse with lysosomes, which enabled bacterial replication. In wild-type macrophages, infection with L. pneumophilia induced the expression of Casp4. Infection of macrophages with a mutant F. pneumophilia deficient in flagellin failed to induce the interaction of caspase-11 with the Nlrc4 inflammasome and to activate caspase-1. Caspase-11 was required for the polymerization of actin around phagosomes containing L. pneumophilia, and F-actin formation depended on caspase-11–mediated inactivation of cofilin. In the absence of F-actin formation, bacterial phagosome fusion with lysosomes was inhibited. Caspase-11 was dispensable for the fusion of lysosomes with phagosomes containing a nonpathogenic strain of Escherichia coli. In a human macrophage cell line that does not contain caspase-11 and cannot eliminate L. pneumophilia, ectopic expression of caspase-4 and caspase-5, human homologs of mouse caspase-11, resulted in activation of caspase-1 and restriction of bacterial replication. Together, these data implicate caspase-11 in the response to pathogenic bacteria by promoting the fusion of bacterial-containing phagosomes with lysosomes as well as activating caspase-1.

A. Akhter, K. Caution, A. A. Khweek, M. Tazi, B. A. Abdulrahman, D. H. A. Abdelaziz, O. H. Voss, A. I. Doseff, H. Hassan, A. K. Azad, L. S. Schlesinger, M. D. Wewers, M. A. Gavrilin, A. O. Amer, Caspase-11 promotes the fusion of phagosomes harboring pathogenic bacteria with lysosomes by modulating actin polymerization. Immunity 37, 35–47 (2012). [PubMed]