SOCS3 Targets Siglec 7 for Proteasomal Degradation and Blocks Siglec 7-mediated Responses

Selinda J. Orr, Nuala M. Morgan, Richard J. Buick, Caroline R. Boyd, Joanne Elliott, James F. Burrows, Caroline A. Jefferies, Paul R. Crocker, James A. Johnston*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

50 Citations (Scopus)
1 Downloads (Pure)

Abstract

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.
Original languageEnglish
Pages (from-to)3418-3422
Number of pages5
JournalJournal of Biological Chemistry
Volume282
Issue number6
Early online date30 Nov 2006
DOIs
Publication statusPublished - 09 Feb 2007

ASJC Scopus subject areas

  • Biochemistry

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