Salt-inducible kinases 1 and 3 negatively regulate Toll-like receptor 4-mediated signal.
Salt-inducible kinases (SIKs) are a family of related serine-threonine kinases and are involved in controlling various metabolisms such as liver glucose homeostasis, hepatic lipogenesis, steroidogenesis, and adipogenesis. Here we investigated the regulatory role of SIK proteins in Toll-like receptor 4 (TLR4)-mediated signaling. Overexpression of SIK1 and SIK3, but not SIK2, significantly inhibited nuclear factor-κB activity in response to lipopolysaccharide stimulation and affected the expression of proinflammatory cytokines. In contrast, both SIK1(KD) and SIK3(KD) Raw 264.7 cells exhibit dramatic elevations of nuclear factor-κB activation and activations of downstream signaling molecules, such as TGF-β-activated kinase 1, p38, and c-Jun N-terminal kinase, in response to TLR4 stimulation, indicating that SIK1 and SIK3 are negatively involved in the TLR4-mediated signaling. Through biochemical studies, we found that SIK1 and SIK3 interact with TGF-β-activated kinase 1-binding protein 2 (TAB2), and interrupt the functional complex of TAB2-TNF receptor-associated factor 6 (TRAF6). Interestingly, the molecular interruption is induced to suppress the ubiquitination of TRAF6 in response to TLR4 stimulation. These result suggest that SIK1 and SIK3 negatively regulate TLR4-mediated signaling through the interruption of TAB2-TRAF6 complex and thereby the inhibition of ubiquitination of TRAF6. The present findings can be useful for a better understanding of multilevel interactions between the metabolic and immune systems.
PhD, Department of Immunology and Infectious Diseases, Harvard School of Public Health, and the Department of Medicine, Harvard Medical School, 665 Huntington Avenue, Building 1, Room 904, Boston, MA 02115 or Ki-Young Lee, PhD, Department of Molecular Cell Biology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 300 Chenocheon-dong, Jangan-gu, Suwon, Gyeonggi-do 440-746, Korea. echun@hsph.harvard.edu; or thylee@skku.edu.
So
S
Yong Kim
Sookyung
S
Jeong
Kyong-Hwa
KH
Chah
Eunyu
E
Jung
Kwan-Hyuck
KH
Baek
Seong-Tae
ST
Kim
Jae-Hyuck
JH
Shim
Eunyoung
E
Chun
Ki-Young
KY
Lee
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D015533:Transcriptional Activation; D054875:Ubiquitination
D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; C498761:Tab2 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D017346:Protein Serine-Threonine Kinases; C571369:SIK3 protein, mouse; C495376:Sik1 protein, mouse