Linked Life Data

20085538

Source:http://linkedlifedata.com/resource/pubmed/id/20085538

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2010-3-15
pubmed:abstractText
Activation of initiator caspases is dependent on interacting proteins, and Ipaf [ICE (interleukin-1beta-converting enzyme)-protease activating factor] {NLRC4 [NLR (Nod-like receptor) family CARD (caspase activation and recruitment domain)-containing 4]} an inflammasome component, is involved in caspase 1 activation and apoptosis. Investigating the mechanisms of Ipaf activation, we found that the C-terminal LRR (leucine-rich repeat) domain of Ipaf, through intramolecular interaction, negatively regulates its apoptosis-inducing function. In A549 lung carcinoma cells, expression of Ac-Ipaf (LRR-domain-deleted Ipaf) induced cell death that was dependent on caspase 8, but not on caspase 1. A yeast two-hybrid screen using Ac-Ipaf as bait identified human Sug1 (suppressor of gal 1), a component of the 26S proteasome, as an interacting protein. In mammalian cells Sug1 interacts and co-localizes with Ipaf. Sug1 binds to amino acids 91-253 of Ipaf, which is also the region that the LRR domain binds to. It potentiates cell death induced by Ipaf and Ac-Ipaf, and co-expression of Sug1 and Ipaf induces caspase-8-dependent cell death. Cellular complexes formed by Ipaf and Sug1 contain caspase 8. Expression of Ac-Ipaf or co-expression of Sug1 with Ipaf results in the formation of cytoplasmic aggregates and caspase 8 activation. Sug1 co-expression enabled modification of Ipaf by ubiquitination. Tagging ubiquitin molecules to Ipaf led to aggregate formation, enhanced caspase 8 interaction and activation, resulting in induction of cell death. Using RNAi (RNA interference) and dominant-negative approaches, we have shown that cell death induced by Ac-Ipaf expression or by treatment with TNF-alpha (tumour necrosis factor alpha) or doxorubicin is dependent on Sug1. Our results suggest a role for ubiquitination of Ipaf that is enabled by its interaction with Sug1, leading to caspase 8 activation and cell death.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
1470-8728
pubmed:author
pubmed:issnType
Electronic
pubmed:day
1
pubmed:volume
427
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
91-104
pubmed:dateRevised
2011-11-17
pubmed:meshHeading
pubmed-meshheading:20085538-Adaptor Proteins, Signal Transducing, pubmed-meshheading:20085538-Blotting, Western, pubmed-meshheading:20085538-Breast Neoplasms, pubmed-meshheading:20085538-CARD Signaling Adaptor Proteins, pubmed-meshheading:20085538-Calcium-Binding Proteins, pubmed-meshheading:20085538-Caspase 8, pubmed-meshheading:20085538-Cell Death, pubmed-meshheading:20085538-Enzyme Activation, pubmed-meshheading:20085538-Female, pubmed-meshheading:20085538-Fluorescent Antibody Technique, pubmed-meshheading:20085538-Humans, pubmed-meshheading:20085538-LIM Domain Proteins, pubmed-meshheading:20085538-Lung Neoplasms, pubmed-meshheading:20085538-RNA, Messenger, pubmed-meshheading:20085538-RNA, Small Interfering, pubmed-meshheading:20085538-Reverse Transcriptase Polymerase Chain Reaction, pubmed-meshheading:20085538-Signal Transduction, pubmed-meshheading:20085538-Transcription Factors, pubmed-meshheading:20085538-Tumor Cells, Cultured, pubmed-meshheading:20085538-Two-Hybrid System Techniques, pubmed-meshheading:20085538-Ubiquitination
pubmed:year
2010
pubmed:articleTitle
Interaction with Sug1 enables Ipaf ubiquitination leading to caspase 8 activation and cell death.
pubmed:affiliation
Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research (CSIR), Uppal Road, Hyderabad 500007, India.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't