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.
Codina
Ramil
R
Department of Microbiology, University of Minnesota Medical School, Minneapolis, MN, USA.
Vanasse
Amelia
A
Kelekar
Ameeta
A
Vezys
Vaiva
V
Jemmerson
Ronald
R
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