SOCS3 targets Siglec 7 for proteasomal degradation and blocks Siglec 7-mediated responses.
CD33-related Siglecs (sialic acid-binding immunoglobulin-like lectins) 5-11 are inhibitory receptors that contain a membrane proximal ITIM (immunoreceptor tyrosine-based inhibitory motif) (I/V/L/)XYXX(L/V), which can recruit SHP-1/2. However, little is known about the regulation of these receptors. SOCS3 (suppressor of cytokine signaling 3) is up-regulated during inflammation and competes with SHP-1/2 for binding to ITIM-like motifs on various cytokine receptors resulting in inhibition of signaling. We show that SOCS3 binds the phosphorylated ITIM of Siglec 7 and targets it for proteasomal-mediated degradation, suggesting that Siglec 7 is a novel SOCS target. Following ligation, the ECS E3 ligase is recruited by SOCS3 to target Siglec 7 for proteasomal degradation, and SOCS3 expression is decreased concomitantly. In addition, we found that SOCS3 expression blocks Siglec 7-mediated inhibition of cytokine-induced proliferation. This is the first time that a SOCS target has been reported to degrade simultaneously with the SOCS protein and that inhibitory receptors have been shown to be degraded in this way. This may be a mechanism by which the inflammatory response is potentiated during infection.
Orr
Selinda J
SJ
Division of Infection and Immunity, Centre for Cancer Research and Cell Biology, Queens University, 97 Lisburn Road, Belfast BT9 7BL, United Kingdom.
Morgan
Nuala M
NM
Buick
Richard J
RJ
Boyd
Caroline R
CR
Elliott
Joanne
J
Burrows
James F
JF
Jefferies
Caroline A
CA
Crocker
Paul R
PR
Johnston
James A
JA
D000818:Animals; D002460:Cell Line; D006801:Humans; D037102:Lectins / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D019158:N-Acetylneuraminic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism* / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D011971:Receptors, Immunologic / Q000378:metabolism; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D015398:Signal Transduction / Q000502:physiology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism
D037102:Lectins; D011971:Receptors, Immunologic; C106644:SOCS3 protein, human; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014443:Tyrosine; D046988:Proteasome Endopeptidase Complex; D019158:N-Acetylneuraminic Acid