Document Detail


Enzymatically active single chain caspase-8 maintains T-cell survival during clonal expansion.
MedLine Citation:
PMID:  20523353     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The extrinsic, or death receptor, pathway integrates apoptotic signals through the protease caspase-8 (casp8). Beyond cell death regulation, non-apoptotic functions of casp8 include its essential requirement for hematopoiesis and lymphocyte clonal expansion, and tempering of autophagy in T cells. However, the mechanistic basis for the control of these disparate cellular processes remains elusive. Here, we show that casp8-deficient T-cell survival was rescued by enzymatically active, but not inactive, casp8-expressing retroviruses. The casp8 catalytic induction in proliferating T cell occurred independent of extrinsic and intrinsic apoptotic-signaling cascades and did not induce casp8 proteolytic processing. Using a biotinylated probe selectively targeting enzymatically active caspases, catalytically active full-length casp8 was found in vivo in dividing T cells. A casp8 D387A processing mutant was able to rescue casp8-deficient T-cell proliferation, validating that casp8 self-processing is not required for its non-apoptotic function(s). Finally, casp8 activity was highest in CD8(+) T cells, the most rapidly proliferating subset. These results show that the catalytically competent form of casp8 is required for rapid T-cell proliferation in response to TCR ligation, but that processing of the caspase is only necessary to promote apoptosis.
Authors:
S Leverrier; G S Salvesen; C M Walsh
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-06-04
Journal Detail:
Title:  Cell death and differentiation     Volume:  18     ISSN:  1476-5403     ISO Abbreviation:  Cell Death Differ.     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2010-12-14     Completed Date:  2011-04-14     Revised Date:  2013-07-31    
Medline Journal Info:
Nlm Unique ID:  9437445     Medline TA:  Cell Death Differ     Country:  England    
Other Details:
Languages:  eng     Pagination:  90-8     Citation Subset:  IM    
Affiliation:
Department of Molecular Biology and Biochemistry, Institute for Immunology, University of California, Irvine, CA 92697-3900, USA.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Substitution
Animals
Apoptosis
CD8-Positive T-Lymphocytes / immunology,  metabolism
Caspase 8 / genetics,  metabolism*
Cell Proliferation
Cell Survival
Fas-Associated Death Domain Protein / metabolism
Mice
Mice, Transgenic
Mutagenesis, Site-Directed
Receptors, Antigen, T-Cell / metabolism
T-Lymphocytes / cytology,  enzymology*,  immunology
Grant Support
ID/Acronym/Agency:
AI50506/AI/NIAID NIH HHS; CA69381/CA/NCI NIH HHS; P30 CA062203/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Fadd protein, mouse; 0/Fas-Associated Death Domain Protein; 0/Receptors, Antigen, T-Cell; EC 3.4.22.-/Caspase 8
Comments/Corrections

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