Document Detail

Receptor signaling lymphocyte-activation molecule family 1 (Slamf1) regulates membrane fusion and NADPH oxidase 2 (NOX2) activity by recruiting a Beclin-1/Vps34/ultraviolet radiation resistance-associated gene (UVRAG) complex.
MedLine Citation:
PMID:  22493499     Owner:  NLM     Status:  MEDLINE    
Phagocytosis is a pivotal process by which macrophages eliminate microorganisms upon recognition by pathogen sensors. Surprisingly, the self-ligand cell surface receptor Slamf1 functions not only as a co-stimulatory molecule but also as a microbial sensor of several Gram-negative bacteria. Upon entering the phagosome of macrophages Slamf1 induces production of phosphatidylinositol 3-phosphate, which positively regulates the activity of the NOX2 enzyme and phagolysosomal maturation. Here, we report that in Escherichia coli-containing phagosomes of mouse macrophages, Slamf1 interacts with the class III PI3K Vps34 in a complex with Beclin-1 and UVRAG. Upon phagocytosis of bacteria the NOX2 activity was reduced in macrophages isolated from Beclin-1(+/-) mice compared with wild-type mice. This Slamf1/Beclin-1/Vps34/UVRAG protein complex is formed in intracellular membrane compartments as it is found without inducing phagocytosis in macrophages, human chronic lymphocytic leukemia cells, and transfectant HEK293 cells. Elimination of its cytoplasmic tail abolished the interaction of Slamf1 with the complex, but deletion or mutation of the two ITAM motifs did not. Both the BD and CCD domains of Beclin-1 were required for efficient binding to Slamf1. Because Slamf1 did not interact with Atg14L or Rubicon, which can also form a complex with Vps34 and Beclin-1, we conclude that Slamf1 recruits a subset of Vps34-associated proteins, which is involved in membrane fusion and NOX2 regulation.
Chunyan Ma; Ninghai Wang; Cynthia Detre; Guoxing Wang; Michael O'Keeffe; Cox Terhorst
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-04-09
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-05-28     Completed Date:  2012-08-15     Revised Date:  2014-09-03    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  18359-65     Citation Subset:  IM    
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MeSH Terms
Antigens, CD / genetics,  physiology*
Apoptosis Regulatory Proteins / genetics*
Cell Line
Class III Phosphatidylinositol 3-Kinases / genetics*
Macrophages / metabolism
Membrane Fusion / physiology*
Membrane Glycoproteins / metabolism*
Membrane Proteins / genetics*
Mice, Knockout
NADPH Oxidase / metabolism*
Phagosomes / metabolism
Receptors, Cell Surface / genetics,  physiology*
Tumor Suppressor Proteins / genetics*
Grant Support
Reg. No./Substance:
0/Antigens, CD; 0/Apoptosis Regulatory Proteins; 0/BECN1 protein, human; 0/Becn1 protein, mouse; 0/CYBB protein, human; 0/Membrane Glycoproteins; 0/Membrane Proteins; 0/Receptors, Cell Surface; 0/Tumor Suppressor Proteins; 0/UVRAG protein, human; 0/UVRAG protein, mouse; 169535-43-7/CD150 antigen; EC protein, mouse; EC Oxidase; EC III Phosphatidylinositol 3-Kinases

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