Document Detail


Identification of two evolutionarily conserved genes regulating processing of engulfed apoptotic cells.
MedLine Citation:
PMID:  20305638     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Engulfment of apoptotic cells occurs throughout life in multicellular organisms. Impaired apoptotic cell clearance (due to defective recognition, internalization or degradation) results in autoimmune disease. One fundamental challenge in understanding how defects in corpse removal translate into diseased states is the identification of critical components orchestrating the different stages of engulfment. Here we use genetic, cell biological and molecular studies in Caenorhabditis elegans and mammalian cells to identify SAND-1 and its partner CCZ-1 as new factors in corpse removal. In worms deficient in either sand-1 or ccz-1, apoptotic cells are internalized and the phagosomes recruit the small GTPase RAB-5 but fail to progress to the subsequent RAB-7(+) stage. The mammalian orthologues of SAND-1, namely Mon1a and Mon1b, were similarly required for phagosome maturation. Mechanistically, Mon1 interacts with GTP-bound Rab5, identifying Mon1 as a previously unrecognized Rab5 effector. Moreover, a Mon1-Ccz1 complex (but not either protein alone) could bind Rab7 and could also influence Rab7 activation, suggesting Mon1-Ccz1 as an important link in progression from the Rab5-positive stage to the Rab7-positive stage of phagosome maturation. Taken together, these data identify SAND-1 (Mon1) and CCZ-1 (Ccz1) as critical and evolutionarily conserved components regulating the processing of ingested apoptotic cell corpses.
Authors:
Jason M Kinchen; Kodi S Ravichandran
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-03-21
Journal Detail:
Title:  Nature     Volume:  464     ISSN:  1476-4687     ISO Abbreviation:  Nature     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-04-02     Completed Date:  2010-05-19     Revised Date:  2011-07-22    
Medline Journal Info:
Nlm Unique ID:  0410462     Medline TA:  Nature     Country:  England    
Other Details:
Languages:  eng     Pagination:  778-82     Citation Subset:  IM    
Affiliation:
Center for Cell Clearance, University of Virginia, Charlottesville, Virginia 22908, USA. kinchen@virginia.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Animals, Genetically Modified
Apoptosis / genetics*
Caenorhabditis elegans / cytology,  genetics
Caenorhabditis elegans Proteins / genetics,  metabolism*
Carrier Proteins / genetics,  metabolism
Cell Line
Conserved Sequence / genetics*
Disorders of Sex Development
Evolution, Molecular*
Gonads / cytology,  metabolism
Guanine Nucleotide Dissociation Inhibitors / metabolism
Hydrogen-Ion Concentration
Mice
Multiprotein Complexes / chemistry,  metabolism
NIH 3T3 Cells
Phagocytosis / genetics*
Phagosomes / genetics,  metabolism
Protein Binding
Thymus Gland / cytology
Two-Hybrid System Techniques
Vesicular Transport Proteins / genetics,  metabolism*
rab GTP-Binding Proteins / metabolism
rab5 GTP-Binding Proteins / metabolism
Grant Support
ID/Acronym/Agency:
R01 GM064709-06/GM/NIGMS NIH HHS; R01 GM064709-07/GM/NIGMS NIH HHS; R01 GM069998-03/GM/NIGMS NIH HHS; R01 GM069998-04/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/CCZ-1 protein, C elegans; 0/Caenorhabditis elegans Proteins; 0/Carrier Proteins; 0/Guanine Nucleotide Dissociation Inhibitors; 0/Mon1a protein, mouse; 0/Mon1b protein, mouse; 0/Multiprotein Complexes; 0/SAND-1 protein, C elegans; 0/Vesicular Transport Proteins; 152989-05-4/rab7 protein; EC 3.6.1.-/rab GTP-Binding Proteins; EC 3.6.5.2/rab5 GTP-Binding Proteins
Comments/Corrections

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