title: Ribotoxic stress through p38 mitogen-activated protein kinase activates in vitro the human pyrin inflammasome.
abstract: Human pyrin with gain-of-function mutations in its B30.2/SPRY domain causes the autoinflammatory disease familial Mediterranean fever by assembling an ASC-dependent inflammasome that activates caspase-1. Wild-type human pyrin can also form an inflammasome complex with ASC after engagement by autoinflammatory PSTPIP1 mutants. How the pyrin inflammasome is activated in the absence of disease-associated mutations is not yet known. We report here that ribotoxic stress triggers the assembly of the human pyrin inflammasome, leading to ASC oligomerization and caspase-1 activation in THP-1 macrophages and in a 293T cell line stably reconstituted with components of the pyrin inflammasome. Knockdown of pyrin and selective inhibition of p38 MAPK greatly attenuated caspase-1 activation by ribotoxic stress, whereas expression of the conditional mutant ΔMEKK3:ER* allowed the activation of caspase-1 without ribotoxic stress. Disruption of microtubules by colchicine also inhibited pyrin inflammasome activation by ribotoxic stress. Together, our results indicate that ribotoxic stress activates the human pyrin inflammasome through a mechanism that requires p38 MAPK signaling and microtubule stability.
authors.affiliation: Department of Biochemistry and Molecular Biology and the Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. jewookyu@yuhs.ac
authors.forename: Je-Wook
authors.initials: JW
authors.lastname: Yu
authors.forename: Andrew
authors.initials: A
authors.lastname: Farias
authors.forename: Inhwa
authors.initials: I
authors.lastname: Hwang
authors.forename: Teresa
authors.initials: T
authors.lastname: Fernandes-Alnemri
authors.forename: Emad S
authors.initials: ES
authors.lastname: Alnemri
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003078:Colchicine / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008870:Microtubules / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D000071198:Pyrin; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology*; D050257:Tubulin Modulators / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; C000604192:MEFV protein, human; C486382:PSTPIP1 protein, human; D000071198:Pyrin; D050257:Tubulin Modulators; D048051:p38 Mitogen-Activated Protein Kinases; D020170:Caspase 1; D003078:Colchicine