Editors' ChoiceCytoskeleton

Does Actin Give the Nod2 to NF-κB Activation?

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Science's STKE  27 Mar 2007:
Vol. 2007, Issue 379, pp. tw101
DOI: 10.1126/stke.3792007tw101

Although it is best known for the structural roles its name suggests, other functions of the actin cytoskeleton have begun to emerge. For instance, in myelomonocytes and intestinal epithelial cells, disruption of the cytoskeleton leads to activation of the transcription factor NF-κB (nuclear factor κB). Nod2 is a cytoplasmic protein that signals through NF-κB to mediate an inflammatory response to bacteria. Noting that Nod2 is selectively expressed in these same two cell types, Legrand-Poels et al. investigated its role in the response to actin disruption. In human embryonic kidney (HEK) 293 cells cotransfected with Nod2 and an NF-κΒ reporter, disruption of the actin cytoskeleton stimulated NF-κB-mediated transcription and specifically potentiated NF-κB activation by a Nod2 ligand. Disruption of the actin cytoskeleton promoted the translocation of actin and Nod2 from detergent-insoluble to detergent-soluble cell fractions; further, immunofluorescence analysis indicated that endogenous Nod2 in HT-29 intestinal epithelial cells--as well as Nod2 expressed ectopically in various cell types--colocalized with F-actin at membrane ruffles and lamellipodia-like structures. Activated Rac1 associated with Nod2 at membrane ruffles; mutational analysis combined with immunofluorescence or coimmunoprecipitation indicated that Nod2 interacted with Rac1 through its two caspase recruitment domains (CARDs) and its leucine-rich repeats (LRRs). A dominant-negative Rac1 mutant that disrupted membrane ruffles (and did not colocalize with Nod2) stimulated NF-κB activity and potentiated NF-κB activation by Nod2. The authors propose that association of Nod2 with dynamic cytoskeletal structures induced by Rac could represent a sequestration mechanism that enables its ready mobilization in response to infection and the subsequent activation of NF-κB.

S. Legrand-Poels, G. Kustermans, F. Bex, E. Kremmer, T. A. Kufer, J. Piette, Modulation of Nod2-dependent NF-κB signaling by the actin cytoskeleton. J. Cell Sci. 120, 1299-1310 (2007). [Abstract] [Full Text]

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