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Ribotoxic Stress through p38 Mitogen-activated Protein Kinase Activates in Vitro the Human Pyrin Inflammasome

Authors
 Je-Wook Yu  ;  Andrew Farias  ;  Inhwa Hwang  ;  Teresa Fernandes-Alnemri  ;  Emad S. Alnemri 
Citation
 JOURNAL OF BIOLOGICAL CHEMISTRY, Vol.288(16) : 11378-11383, 2013 
Journal Title
 JOURNAL OF BIOLOGICAL CHEMISTRY 
ISSN
 0021-9258 
Issue Date
2013
MeSH
Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Caspase 1/genetics ; Caspase 1/metabolism ; Cell Line ; Colchicine/pharmacology ; Cytoskeletal Proteins/genetics ; Cytoskeletal Proteins/metabolism* ; Humans ; Inflammasomes/genetics ; Inflammasomes/metabolism* ; MAP Kinase Signaling System/drug effects ; MAP Kinase Signaling System/physiology* ; Microtubules/genetics ; Microtubules/metabolism ; Mutation ; Pyrin ; Stress, Physiological/drug effects ; Stress, Physiological/physiology* ; Tubulin Modulators/pharmacology ; p38 Mitogen-Activated Protein Kinases/genetics ; p38 Mitogen-Activated Protein Kinases/metabolism*
Keywords
Inflammation ; MAP Kinases (MAPKs) ; p38 ; Ribosomes ; Stress ; Pyrin ; Caspase-1 ; Familial Mediterranean Fever ; Inflammasome ; Ribotoxic Stress
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.
Files in This Item:
T201301294.pdf Download
DOI
10.1074/jbc.M112.448795
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Yu, Je Wook(유제욱) ORCID logo https://orcid.org/0000-0001-5943-4071
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/86747
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