Cytochrome c-induced lymphocyte death from the outside in: inhibition by serum leucine-rich alpha-2-glycoprotein-1.
Previously we reported that serum leucine-rich alpha-2-glycoprotein-1 (LRG) binds cytochrome c (Cyt c; Cummings et al., Apoptosis 11:1121-1129, 2009). Here we show that LRG binding to Cyt c is similar to that of Apaf-1. LRG and Apaf-1 share partial amino acid sequences, compete for binding Cyt c, and are inhibited by modification at lysine 72 in Cyt c. However, in contrast to Apaf-1, LRG acts as a survival factor in vitro rather than a pro-apoptotic factor. By depleting LRG from culture medium we found that LRG protects against a toxic effect of exogenous Cyt c on lymphocytes that would otherwise result in an apoptotic phenotype. LRG, as well as antibodies specific for Cyt c, increased cell viability in the absence of added Cyt c indicating that Cyt c released by dying cells in the cultures is itself toxic. Protection from extracellular Cyt c-induced lymphotoxicity appears to involve an active mechanism rather than steric hindrance of Cyt c. Thus, serum LRG when bound to extracellular Cyt c that is released from apoptotic cells acts as a survival factor for lymphocytes and possibly other cells that are susceptible to the toxic effect of extracellular Cyt c.
Department of Microbiology, University of Minnesota Medical School, Minneapolis, MN, USA.
Ramil
R
Codina
Amelia
A
Vanasse
Ameeta
A
Kelekar
Vaiva
V
Vezys
Ronald
R
Jemmerson
D000595:Amino Acid Sequence; D000818:Animals; D053477:Apoptotic Protease-Activating Factor 1 / Q000737:chemistry / Q000378:metabolism; D001667:Binding, Competitive; D016923:Cell Death; D002470:Cell Survival; D002478:Cells, Cultured; D017124:Conserved Sequence; D045304:Cytochromes c / Q000378:metabolism*; D019143:Evolution, Molecular; D005434:Flow Cytometry; D006023:Glycoproteins / Q000097:blood* / Q000737:chemistry; D006736:Horses; D006801:Humans; D008214:Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010641:Phenotype; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity
C506592:APAF1 protein, human; D053477:Apoptotic Protease-Activating Factor 1; D006023:Glycoproteins; C015246:LRG1 protein, human; D045304:Cytochromes c; D008239:Lysine