Down syndrome candidate region-1 protein interacts with Tollip and positively modulates interleukin-1 receptor-mediated signaling

The Down syndrome candidate region-1 gene ( DSCR1, also known as RCAN1) is situated close to the Down Syndrome Critical Region (DSCR), which contains genes responsible for many features of Down syndrome. DSCR1 modulates calcineurin phosphatase activity, though its functional role is incompletely und...

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Published in:Biochimica et biophysica acta Vol. 1790; no. 12; pp. 1673 - 1680
Main Authors: Lee, Jae Youn, Lee, Hyun Jung, Lee, Eun Jung, Jang, Sung Hee, Kim, Hyeyoung, Yoon, Joo-Heon, Chung, Kwang Chul
Format: Journal Article
Language:English
Published: Netherlands Elsevier B.V 01.12.2009
Subjects:
Cells, Cultured
Cytokine
Down syndrome
Down Syndrome Critical Region
Humans
IL-1
Inflammation
Interleukin-1 Receptor-Associated Kinases - metabolism
Interleukin-8 - metabolism
Intracellular Signaling Peptides and Proteins - chemistry
Intracellular Signaling Peptides and Proteins - metabolism
Intracellular Signaling Peptides and Proteins - physiology
Models, Biological
Muscle Proteins - chemistry
Muscle Proteins - metabolism
Muscle Proteins - physiology
NF-kappa B - metabolism
Protein Binding
Protein Interaction Domains and Motifs - physiology
Protein Isoforms - metabolism
Protein Isoforms - physiology
Receptors, Interleukin-1 - metabolism
Receptors, Interleukin-1 - physiology
Signal Transduction - physiology
TNF Receptor-Associated Factor 6 - metabolism
Tollip
Up-Regulation
Inflammation
Down syndrome
Down Syndrome Critical Region
IL-1
Cytokine
Tollip
ISSN:0304-4165, 0006-3002, 1872-8006
Online Access:Get full text
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Summary:The Down syndrome candidate region-1 gene ( DSCR1, also known as RCAN1) is situated close to the Down Syndrome Critical Region (DSCR), which contains genes responsible for many features of Down syndrome. DSCR1 modulates calcineurin phosphatase activity, though its functional role is incompletely understood. Here we investigated the role of DSCR1-1S isoform in IL-1 receptor (IL-1R)-mediated signaling by analyzing interaction between DSCR1-1S and the IL-1R pathway components Tollip, IRAK-1, and TRAF6. Co-immunoprecipitation analyses of HEK293 cells revealed that DSCR1-1S interacted with Tollip, an IRAK-1 inhibitor, leading to the dissociation of IRAK-1 from Tollip. Similarly, both DSCR1-1S and Tollip interacted with TRAF6, with DSCR1 reducing interaction between Tollip and TRAF6. DSCR1-1S also stimulated IL-1R-mediated signaling pathways, TAK1 activation, NF-κB transactivation, and IL-8 production, all downstream consequences of IL-1R activation. Together, these results suggest that DSCR1-1S isoform positively modulates IL-1R-mediated signaling pathways by regulating Tollip/IRAK-1/TRAF6 complex formation.
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ISSN:0304-4165
0006-3002
1872-8006
DOI:10.1016/j.bbagen.2009.08.005