The Journal of Experimental Medicine
Torrey Pines Biolabs
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
Published 16 December 2002. doi:10.1084/jem.20021552
This Article
Right arrow Full Text
Right arrow Full Text (PDF, 461K)
Right arrow PPT slides of all figures
Right arrow Alert me when this article is cited
Right arrow Citation Map
Services
Right arrow Email this article
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new content in the JEM
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Stehlik, C.
Right arrow Articles by Reed, J. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Stehlik, C.
Right arrow Articles by Reed, J. C.
Right arrowPubmed/NCBI databases
*Gene*GEO Profiles
*HomoloGene*UniGene
*Compound via MeSH
*Substance via MeSH
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?
© Rockefeller University Press, 0022-1007/2002/12/1605/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 12, December 16, 2002 1605-1615

The PAAD/PYRIN-Family Protein ASC Is a Dual Regulator of a Conserved Step in Nuclear Factor {kappa}B Activation Pathways

Christian Stehlik1, Loredana Fiorentino1, Andrea Dorfleutner2, Jean-Marie Bruey1, Eugenia M. Ariza1, Junji Sagara3 and John C. Reed1

1 The Burnham Institute, The Scripps Research Institute, La Jolla, CA 92037
2 Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
3 Department of Molecular Oncology, Research Center on Aging and Adaptation, Shinshu University School of Medicine, Nagano 390-8621, Japan

Address correspondence to John C. Reed, The Burnham Institute, 10901 North Torrey Pines Rd., La Jolla, CA 92037. Phone: 858-646-3140; Fax: 858-646-3194; E-mail: jreed{at}burnham.org

Apoptosis-associated speck-like protein containing a Caspase recruitment domain (ASC) belongs to a large family of proteins that contain a Pyrin, AIM, ASC, and death domain-like (PAAD) domain (also known as PYRIN, DAPIN, Pyk). Recent data have suggested that ASC functions as an adaptor protein linking various PAAD-family proteins to pathways involved in nuclear factor (NF)-{kappa}B and pro-Caspase-1 activation. We present evidence here that the role of ASC in modulating NF-{kappa}B activation pathways is much broader than previously suspected, as it can either inhibit or activate NF-{kappa}B, depending on cellular context. While coexpression of ASC with certain PAAD-family proteins such as Pyrin and Cryopyrin increases NF-{kappa}B activity, ASC has an inhibitory influence on NF-{kappa}B activation by various proinflammatory stimuli, including tumor necrosis factor (TNF){alpha}, interleukin 1ß, and lipopolysaccharide (LPS). Elevations in ASC protein levels or of the PAAD domain of ASC suppressed activation of I{kappa}B kinases in cells exposed to pro-inflammatory stimuli. Conversely, reducing endogenous levels of ASC using siRNA enhanced TNF- and LPS-induced degradation of the IKK substrate, I{kappa}B{alpha}. Our findings suggest that ASC modulates diverse NF-{kappa}B induction pathways by acting upon the IKK complex, implying a broad role for this and similar proteins containing PAAD domains in regulation of inflammatory responses.

Key Words: inflammation • signal transduction • I{kappa}B kinase • monocytes • NF-{kappa}B


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:



  Home | Help | Feedback | Subscriptions | Archive | Search
TABLE OF CONTENTS