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


METHODS
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.


RESULTS
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-kappaB transactivation, and IL-8 production, all downstream consequences of IL-1R activation.


CONCLUSIONS
Together, these results suggest that DSCR1-1S isoform positively modulates IL-1R-mediated signaling pathways by regulating Tollip/IRAK-1/TRAF6 complex formation.
Lee
Jae Youn
JY
Department of Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
Lee
Hyun Jung
HJ
Lee
Eun Jung
EJ
Jang
Sung Hee
SH
Kim
Hyeyoung
H
Yoon
Joo-Heon
JH
Chung
Kwang Chul
KC
D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology*; D008954:Models, Biological; D009124:Muscle Proteins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D020033:Protein Isoforms / Q000378:metabolism / Q000502:physiology; D017472:Receptors, Interleukin-1 / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D016328:NF-kappa B; D020033:Protein Isoforms; C108612:RCAN1 protein, human; D017472:Receptors, Interleukin-1; D048029:TNF Receptor-Associated Factor 6; C410602:TOLLIP protein, human; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases