SPOTS: signaling protein oligomeric transduction structures are early mediators of death receptor-induced apoptosis at the plasma membrane.
Fas (CD95, APO-1, TNFRSF6) is a TNF receptor superfamily member that directly triggers apoptosis and contributes to the maintenance of lymphocyte homeostasis and prevention of autoimmunity. Although FADD and caspase-8 have been identified as key intracellular mediators of Fas signaling, it is not clear how recruitment of these proteins to the Fas death domain leads to activation of caspase-8 in the receptor signaling complex. We have used high-resolution confocal microscopy and live cell imaging to study the sequelae of early events in Fas signaling. These studies have revealed a new stage of Fas signaling in which receptor ligation leads to the formation of surface receptor oligomers that we term signaling protein oligomerization transduction structures (SPOTS). Formation of SPOTS depends on the presence of an intact Fas death domain and FADD but is independent of caspase activity. Analysis of cells expressing Fas mutations from patients with the autoimmune lymphoproliferative syndrome (ALPS) reveals that formation of SPOTS can be disrupted by distinct mechanisms in ALPS.
Siegel
Richard M
RM
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. rsiegel@nih.gov
Muppidi
Jagan R
JR
Sarker
Malabika
M
Lobito
Adrian
A
Jen
Melinda
M
Martin
David
D
Straus
Stephen E
SE
Lenardo
Michael J
MJ
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D029681:Arabidopsis Proteins / Q000378:metabolism; D019556:COS Cells; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D021961:Cell Membrane Structures / Q000378:metabolism*; D044943:Fatty Acid Desaturases / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
D029681:Arabidopsis Proteins; D011956:Receptors, Cell Surface; D019014:fas Receptor; D044943:Fatty Acid Desaturases; C084083:Fad7 protein, Arabidopsis; D020169:Caspases