The pyrin inflammasome: from sensing RhoA GTPases-inhibiting toxins to triggering autoinflammatory syndromes

Abstract

Numerous pathogens including Clostridium difficile and Yersinia pestis have evolved toxins or effectors targeting GTPases from the RhoA subfamily (RhoA/B/C) to inhibit or hijack the host cytoskeleton dynamics. The resulting impairment of RhoA GTPases activity is sensed by the host via an innate immune complex termed the pyrin inflammasome in which caspase-1 is activated. The cascade leading to activation of the pyrin inflammasome has been recently uncovered. In this review, following a brief presentation of RhoA GTPases-modulating toxins, we present the pyrin inflammasome and its regulatory mechanisms. Furthermore, we discuss how some pathogens have developed strategies to escape detection by the pyrin inflammasome. Finally, we present five monogenic autoinflammatory diseases associated with pyrin inflammasome deregulation. The molecular insights provided by the study of these diseases and the corresponding mutations on pyrin inflammasome regulation and activation are presented.

Role of inflammasomes in the pathogenesis of periodontal disease and therapeutics

“…Pyrin does not directly sense modified RhoA, but rather senses impairment of RhoA activity from RhoA modifications, sequestration of RhoA or stimulation of its GTPase activity. 51 Like the other inflammasomes described here, activation of pyrin recruits the linker ASC binding through pyrin domain-pyrin domain binding. ASC then oligomerizes, followed by caspase-1 recruitment and activation.…”

“…The RhoA family regulates actin cytoskeletal dynamics that many bacterial pathogens modify in order to invade host cells for their survival. Pyrin does not directly sense modified RhoA, but rather senses impairment of RhoA activity from RhoA modifications, sequestration of RhoA or stimulation of its GTPase activity . Like the other inflammasomes described here, activation of pyrin recruits the linker ASC binding through pyrin domain‐pyrin domain binding.…”

“…It is the protein for which the pyrin domain was named. It has an N‐terminal pyrin domain, then a long linker, followed by a B‐box, a coil‐coil domain and finally a B30.2 at the C‐terminus . The pyrin inflammasome recognizes inhibition of the Rho family of GTPases.…”

“…It has an N-terminal pyrin domain, then a long linker, followed by a B-box, a coil-coil domain and finally a B30.2 at the C-terminus. 51 The pyrin inflammasome recognizes inhibition of the Rho family of GTPases. The RhoA family regulates actin cytoskeletal dynamics that many bacterial pathogens modify in order to invade host cells for their survival.…”

Inflammasomes in the pathophysiology of autoinflammatory syndromes

“…B), but only 14 occur frequently in FMF (E148Q, E167D, T267I, P369S, F479L, I591T, M680I, I692del, M694I, M694V, K695R, V726A, A744S, and R761H). Interestingly, in contrast to the gain‐of‐function mutations in NLRP3, NLRC4, or NLRP1 observed in CAPS and in NLRC4‐ and NLRP1‐associated inflammasomopathies, FMF‐associated MEFV mutations do not lead to constitutive pyrin inflammasome activation and require a specific stimulus, such as low doses of Clostridium difficile toxin B . Most pathogenic MEFV mutations in humans occur in exon 10, which encodes the B30.2 domain.…”