Editors' ChoiceInnate Immunity

Detecting a Pathogenic Activity, Not a Pathogenic Molecule

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Science Signaling  16 Sep 2014:
Vol. 7, Issue 343, pp. ec252
DOI: 10.1126/scisignal.2005897

Cells form inflammasomes—cytosolic, multiprotein aggregates—in response to the intracellular presence of various inflammatory compounds. Inflammasomes consist of a pattern-recognition receptor (PRR) that binds to the inflammatory compound, the adaptor protein Asc, and pro-caspase 1. Oligomerization of inflammasome components results in caspase 1 activation and the processing and secretion of pro-inflammatory cytokines. Xu et al. found that the candidate PRR pyrin mediated inflammasome activation in cells exposed to the Clostridium difficile virulence factor TcdB, a glucosyltransferase that modifies and inactivates members of the Rho family of guanosine triphosphatases (GTPases). Mouse bone marrow–derived macrophages (BMDMs) incubated with wild-type TcdB, but not a glucosyltransferase-defective mutant TcdB, exhibited caspase 1 activation. Human embryonic kidney (HEK) 293 cells treated with wild-type TcdB formed aggregates of Asc, and TcdB-driven aggregation of Asc required pyrin but not other PRRs. BMDMs treated with Rho GTPase–modifying toxins from other bacteria also exhibited caspase 1 activation; however, catalytically inactive mutants of these toxins failed to activate the inflammasome. All of these toxins modified residues in the switch I region of Rho GTPases. Knockdown of all Rho isoforms in HEK 293 cells prevented TcdB from triggering Asc aggregation. Whereas reconstitution of these cells with wild-type RhoA rescued TcdB-stimulated Asc aggregation, reconstitution with a modification-site mutant of RhoA did not. TcdB did not induce a physical association between pyrin and Rho proteins. Infection of macrophages with wild-type Burkholderia cenocepacia, but not a strain deficient in its Rho-modifying toxin, caused inactivation of RhoA by deamidation of Asn41 in the switch I region, as well as activation of caspase 1. Both Asc and pyrin were required for inflammasome activation by B. cenocepacia, and bacterial replication was increased in pyrin-deficient macrophages compared with that in wild-type macrophages. Together, these data suggest that rather than directly detecting a microbial product to induce inflammasome activation, pyrin responds to the consequences of modification and inactivation of the host’s Rho family members by toxins produced by the infecting bacteria.

H. Xu, J. Yang, W. Gao, L. Li, P. Li, L. Zhang, Y.-N. Gong, X. Peng, J. J. Xi, S. Chen, F. Wang, F. Shao, Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome. Nature 513, 237–241 (2014). [PubMed]