RhoGTPases and inflammasomes: Guardians of effector-triggered immunity

Abstract

Pathogens have evolved smart strategies to invade hosts and hijack their immune responses. One such strategy is the targeting of the host RhoGTPases by toxins or virulence factors to hijack the cytoskeleton dynamic and immune processes. In response to this microbial attack, the host has evolved an elegant strategy to monitor the function of virulence factors and toxins by sensing the abnormal activity of RhoGTPases. This innate immune strategy of sensing bacterial effector targeting RhoGTPase appears to be a bona fide example of effector-triggered immunity (ETI). Here, we review recently discovered mechanisms by which the host can sense the activity of these toxins through NOD and NOD-like receptors (NLRs).

Fig 1. Sensing of RhoGTPase-modifying toxins by Pyrin and NLRP3 inflammasomes.

(Left) The Pyrin inflammasome is activated in response to RhoA inhibition by several bacterial toxins. At steady state, active RhoA induces the activation of PKN1/2 that phosphorylates (P) Pyrin (on Ser205 and Ser241) and triggers 14-3-3—Pyrin interaction to maintain Pyrin inactive. Inhibition of RhoA by virulence factors disrupts this interaction leading to Pyrin inflammasome activation and subsequent IL-1ß maturation and GSDMD cleavage into GSDMD-N. GSDMD-N anchors to the plasma membrane and triggers IL-1ß secretion and pyroptotic cell death. The involvement of ESCRT-mediated membrane repair during Pyrin-dependent pyroptosis is not yet defined. (Right) The NLRP3 inflammasome senses Rac2 activation by bacterial virulence factors. Downstream of Rac2 activation, the Pak1/2 kinases phosphorylate (P) NLRP3 on Thr659 allowing the inflammasome assembly, and subsequent IL-1ß maturation. Is this context, IL-1ß secretion is GSDMD independent and does not trigger cell death but may involve another GSDM and/or an ESCRT-dependent membrane repair mechanism. GSDM, gasdermin; GSDMD, gasdermin D; IL, interleukin.