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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 ; Emad S. Alnemri ; Teresa Fernandes-Alnemri ; Inhwa Hwang 
Citation
 Journal of Biological Chemistry, Vol.288(16) : 11378~11383, 2013 
Journal Title
 Journal of Biological Chemistry 
ISSN
 0021-9258 
Issue Date
2013
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.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/86747
DOI
10.1074/jbc.M112.448795
Appears in Collections:
1. 연구논문 > 1. College of Medicine > Dept. of Microbiology
Yonsei Authors
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