New knowledge on the role of RhoA in the modulation of the pyrin inflammasome opened the way to a better understanding of two apparently unrelated autoinflammatory disorders: Familial Mediterranean Fever (FMF; OMIM#249100) and Mevalonate Kinase Deficiency (MKD; OMIM#260920). RhoA (Ras homolog gene family, member A) is a sensor of innate immunity, which transduces signals after binding of bacterial toxins and other danger signals. Recent data showed that the signaling cascade of RhoA is based on the regulation of cytoskeletal microtubules and regulation of pyrin. RhoA functions as an inhibitor of the pyrin inflammasome. Thus, inhibition of RhoA by bacterial stimuli results in activation of pyrin, while activation of RhoA by drugs such as colchicine results in inhibition of pyrin-mediated inflammation. FMF is due to mutations in the pyrin domain that cause a constitutive activation of pyrin. FMF mutations did not completely prevent pyrin from the inhibitory effect from RhoA. Thus, therapeutic approaches to RhoA signaling may play a role in the treatment of the disease. MKD is caused by mutations in mevalonate kinase and correlate with an impaired prenylation of RhoA, which is reflected on a lack of pyrin inhibition and on autoinflammation. The new knowledge on RhoA establishes an unpredicted connection between these two autoinflammatory disorders.

New Mechanisms in Autoinflammatory Diseases

Annalisa Marcuzzi
;
Elisa Piscianz;Erica Valencic;Alberto Tommasini
2017

Abstract

New knowledge on the role of RhoA in the modulation of the pyrin inflammasome opened the way to a better understanding of two apparently unrelated autoinflammatory disorders: Familial Mediterranean Fever (FMF; OMIM#249100) and Mevalonate Kinase Deficiency (MKD; OMIM#260920). RhoA (Ras homolog gene family, member A) is a sensor of innate immunity, which transduces signals after binding of bacterial toxins and other danger signals. Recent data showed that the signaling cascade of RhoA is based on the regulation of cytoskeletal microtubules and regulation of pyrin. RhoA functions as an inhibitor of the pyrin inflammasome. Thus, inhibition of RhoA by bacterial stimuli results in activation of pyrin, while activation of RhoA by drugs such as colchicine results in inhibition of pyrin-mediated inflammation. FMF is due to mutations in the pyrin domain that cause a constitutive activation of pyrin. FMF mutations did not completely prevent pyrin from the inhibitory effect from RhoA. Thus, therapeutic approaches to RhoA signaling may play a role in the treatment of the disease. MKD is caused by mutations in mevalonate kinase and correlate with an impaired prenylation of RhoA, which is reflected on a lack of pyrin inhibition and on autoinflammation. The new knowledge on RhoA establishes an unpredicted connection between these two autoinflammatory disorders.
lug-2017
Pubblicato
File in questo prodotto:
File Dimensione Formato  
Focus on autoinflammatory disorders.pdf

non disponibili

Tipologia: Documento in Versione Editoriale
Licenza: Digital Rights Management non definito
Dimensione 388.75 kB
Formato Adobe PDF
388.75 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11368/2915002
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact