A dRAStic RHOAdblock of Pyrin inflammasome activation

Abstract

The Pyrin inflammasome guard is disabled if the activity of small cellular GTPase is compromised, in response to defects in the mevalonate pathway and directly by mutations in Pyrin, resulting in the IL-1β-driven autoinflammatory diseases MKD and FMF.

Figure 1. The guard-type Pyrin inflammasome

(a) Bacterial toxins, such as TcdB, C3, VopS and IbpA or intracellular cAMP cause inactivation of RhoA and consequently disrupt PKN-mediated phosphorylation of Pyrin, which releases the 14-3-3 protein guards from Pyrin to promote assembly of the Pyrin inflammasome and release IL-1β and IL-18 to support host defense against these bacterial pathogens. (b), Deficiency in the mevalonate kinase (MVK) as in MKD/HIDS patients impairs Kras geranylgeranylation, Kras binding and activation of Akt1 and subsequently causes elevated pro-inflammatory cytokine release and MEFV expression. In parallel, geranylgeranylation-dependent RhoA activation is impaired, which releases the 14-3-3 guard from Pyrin and causes constitutive and chronic Pyrin inflammasome assembly and activation and excessive release of IL-1β. Similarly, hereditary mutations in Pyrin, as observed in FMF patients, prevent interaction with PKNs and 14-3-3 proteins or directly destroy the serine 242 phosphorylation site, as observed in PAAND patients, resulting in excessive Pyrin inflammasome activation. Hence, temporary disruption of any part of this guard pathway causes Pyrin-dependent host defense responses, while constant disruption by genetic mutations causes IL-1β-depended auto-inflammatory disease. (c) During homeostasis, sufficient geranylgeranyl pyrophosphate is generated through the metabolic mevalonate pathway through the activities of MVK and the geranylgeranyl transferase I (GGTase I) to appropriately geranylgeranylate small GTPases, including Kras and RhoA to tether them to the plasma membrane. Active, geranylgeranylated Kras regulates TLR-mediated PI3K/Akt1activation to balance transcription of pro-inflammatory and anti-inflammatory mediators and downregulates MEFV expression. At the same time activation of the RhoA effector kinases PKN1 and PKN2 results in phosphorylation of Pyrin on serine 208 and 242 and enables interaction with members of the 14-3-3 family, which guard activation of Pyrin.