A novel function of Siglec-9 A391C polymorphism on T cell receptor signaling.
BACKGROUND
Sialic-acid-binding immunoglobulin-like lectins (Siglecs) are the best-characterized immunoglobulin-type lectins. There is a growing amount of data linking Siglec and autoimmune diseases. The recently identified Siglec-9 inhibits T cell receptor (TCR)-mediated signaling which has been demonstrated by site-directed mutagenesis. In human Siglec-9, at least 8 nonsynonymous SNPs have been detected without functional studies. This study examined the SNP(s) related to TCR-mediated signaling.


METHODS
Since the functions of Siglecs are modulated by their interaction with sialic-acid-containing carbohydrate groups, a molecular modeling analysis of carbohydrate binding interactions and an RBC binding analysis were performed using the 8 SNPs. The TCR-mediated signaling was analyzed with the downstream signaling molecules ZAP-70 and IL-2.


RESULTS
This study revealed that an A391C polymorphism is the only mutant related to the binding. Jurkat T cells transfected with the A391C mutant reduced the inhibition of ZAP-70 phosphorylation and IL-2 production compared to cells transfected with the wild type.


CONCLUSIONS
Siglec-9 A391C was the only polymorphism related to TCR-mediated signaling in human Siglec-9, resulting in less inhibition compared to the wild type.
Cheong
Kyung Ah
KA
Department of Dermatology, Dongguk University Ilsan Hospital, Ilsandong-gu, Goyang, Korea.
Chang
Yoon-Seok
YS
Roh
Joo Young
JY
Kim
Bum-Jun
BJ
Kim
Myung-Nam
MN
Park
Youn Min
YM
Park
Hai Jin
HJ
Kim
Nam-Doo
ND
Lee
Chang-Hoon
CH
Lee
Ai-Young
AY
D015703:Antigens, CD / Q000235:genetics* / Q000276:immunology; D015153:Blotting, Western; D004912:Erythrocytes / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology; D019169:Jurkat Cells; D037102:Lectins / Q000235:genetics* / Q000276:immunology; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D019158:N-Acetylneuraminic Acid / Q000276:immunology; D010766:Phosphorylation / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D015398:Signal Transduction; D014162:Transfection; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000276:immunology
D015703:Antigens, CD; D007376:Interleukin-2; D037102:Lectins; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; C412227:SIGLEC9 protein, human; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D051746:ZAP-70 Protein-Tyrosine Kinase; D019158:N-Acetylneuraminic Acid