Cereblon negatively regulates TLR4 signaling through the attenuation of ubiquitination of TRAF6

DSpace/Manakin Repository

Cereblon negatively regulates TLR4 signaling through the attenuation of ubiquitination of TRAF6

Citable link to this page

 

 
Title: Cereblon negatively regulates TLR4 signaling through the attenuation of ubiquitination of TRAF6
Author: Min, Yoon; Wi, Sae Mi; Kang, Jung-Ah; Yang, Taewoo; Park, Chul-Seung; Park, Sung-Gyoo; Chung, Sungkwon; Shim, Jae-Hyuck; Chun, Eunyoung; Lee, Ki-Young

Note: Order does not necessarily reflect citation order of authors.

Citation: Min, Yoon, Sae Mi Wi, Jung-Ah Kang, Taewoo Yang, Chul-Seung Park, Sung-Gyoo Park, Sungkwon Chung, Jae-Hyuck Shim, Eunyoung Chun, and Ki-Young Lee. 2016. “Cereblon negatively regulates TLR4 signaling through the attenuation of ubiquitination of TRAF6.” Cell Death & Disease 7 (7): e2313. doi:10.1038/cddis.2016.226. http://dx.doi.org/10.1038/cddis.2016.226.
Full Text & Related Files:
Abstract: Cereblon (CRBN) is a substrate receptor protein for the CRL4A E3 ubiquitin ligase complex. In this study, we report on a new regulatory role of CRBN in TLR4 signaling. CRBN overexpression leads to suppression of NF-κB activation and production of pro-inflammatory cytokines including IL-6 and IL-1β in response to TLR4 stimulation. Biochemical studies revealed interactions between CRBN and TAK1, and TRAF6 proteins. The interaction between CRBN and TAK1 did not affect the association of the TAB1 and TAB2 proteins, which have pivotal roles in the activation of TAK1, whereas the CRBN-TRAF6 interaction critically affected ubiquitination of TRAF6 and TAB2. Binding mapping results revealed that CRBN interacts with the Zinc finger domain of TRAF6, which contains the ubiquitination site of TRAF6, leading to attenuation of ubiquitination of TRAF6 and TAB2. Functional studies revealed that CRBN-knockdown THP-1 cells show enhanced NF-κB activation and p65- or p50-DNA binding activities, leading to up-regulation of NF-κB-dependent gene expression and increased pro-inflammatory cytokine levels in response to TLR4 stimulation. Furthermore, Crbn−/− mice exhibit decreased survival in response to LPS challenge, accompanied with marked enhancement of pro-inflammatory cytokines, such as TNF-α and IL-6. Taken together, our data demonstrate that CRBN negatively regulates TLR4 signaling via attenuation of TRAF6 and TAB2 ubiquitination.
Published Version: doi:10.1038/cddis.2016.226
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973362/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:29002653
Downloads of this work:

Show full Dublin Core record

This item appears in the following Collection(s)

 
 

Search DASH


Advanced Search
 
 

Submitters