Document Detail

Caspase cleavage of the Golgi stacking factor GRASP65 is required for Fas/CD95-mediated apoptosis.
MedLine Citation:
PMID:  21368855     Owner:  NLM     Status:  MEDLINE    
GRASP65 (Golgi reassembly and stacking protein of 65 KDa) is a cis-Golgi protein with roles in Golgi structure, membrane trafficking and cell signalling. It is cleaved by caspase-3 early in apoptosis, promoting Golgi fragmentation. We now show that cleavage is needed for Fas-mediated apoptosis: expression of caspase-resistant GRASP65 protects cells, whereas expression of membrane proximal caspase-cleaved GRASP65 fragments dramatically sensitises cells. GRASP65 coordinates passage through the Golgi apparatus of proteins containing C-terminal hydrophobic motifs, via its tandem PDZ type 'GRASP' domains. Fas/CD95 contains a C-terminal leucine-valine pairing so its trafficking might be coordinated by GRASP65. Mutagenesis of the Fas/CD95 LV motif reduces the number of cells with Golgi-associated Fas/CD95, and generates a receptor that is more effective at inducing apoptosis; however, siRNA-mediated silencing or expression of mutant GRASP65 constructs do not alter the steady state distribution of Fas/CD95. We also find no evidence for a GRASP65-Fas/CD95 interaction at the molecular level. Instead, we find that the C-terminal fragments of GRASP65 produced following caspase cleavage are targeted to mitochondria, and ectopic expression of these sensitises HeLa cells to Fas ligand. Our data suggest that GRASP65 cleavage promotes Fas/CD95-mediated apoptosis via release of C-terminal fragments that act at the mitochondria, and we identify Bcl-X(L) as a candidate apoptotic binding partner for GRASP65.
J P X Cheng; V M S Betin; H Weir; G M A Shelmani; D K Moss; J D Lane
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-10-07
Journal Detail:
Title:  Cell death & disease     Volume:  1     ISSN:  2041-4889     ISO Abbreviation:  Cell Death Dis     Publication Date:  2010  
Date Detail:
Created Date:  2011-03-03     Completed Date:  2011-06-14     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  101524092     Medline TA:  Cell Death Dis     Country:  England    
Other Details:
Languages:  eng     Pagination:  e82     Citation Subset:  IM    
Cell Biology Laboratories, School of Biochemistry, University of Bristol, UK.
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MeSH Terms
Amino Acid Sequence
Antigens, CD95 / metabolism*
Caspases / metabolism*
Fas Ligand Protein / pharmacology
Golgi Apparatus / metabolism
HeLa Cells
Membrane Proteins / chemistry,  genetics,  metabolism*
Molecular Sequence Data
Protein Binding
Protein Structure, Tertiary
RNA Interference
RNA, Small Interfering / metabolism
Signal Transduction
Thapsigargin / pharmacology
bcl-X Protein / metabolism
Grant Support
074208//Wellcome Trust; //Biotechnology and Biological Sciences Research Council
Reg. No./Substance:
0/Antigens, CD95; 0/Fas Ligand Protein; 0/GORASP1 protein, human; 0/Membrane Proteins; 0/RNA, Small Interfering; 0/bcl-X Protein; 67526-95-8/Thapsigargin; EC 3.4.22.-/Caspases

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