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SPOP negatively regulates Toll-like receptor-induced inflammation by disrupting MyD88 self-association

Toll-like receptor (TLR) signaling pathways need to be tightly controlled to avoid excessive inflammation and unwanted damage to the host. Myeloid differentiation primary response gene 88 (MyD88) is a critical adaptor of TLR signaling. Here, we identified the speckle-type POZ protein (SPOP) as a MyD...

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Autores principales: Hu, Yun-Hong, Wang, Yang, Wang, Fei, Dong, Yan-Ming, Jiang, Wan-Ling, Wang, Ya-Ping, Zhong, Xing, Ma, Li-Xin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245473/
https://www.ncbi.nlm.nih.gov/pubmed/32235916
http://dx.doi.org/10.1038/s41423-020-0411-1
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author Hu, Yun-Hong
Wang, Yang
Wang, Fei
Dong, Yan-Ming
Jiang, Wan-Ling
Wang, Ya-Ping
Zhong, Xing
Ma, Li-Xin
author_facet Hu, Yun-Hong
Wang, Yang
Wang, Fei
Dong, Yan-Ming
Jiang, Wan-Ling
Wang, Ya-Ping
Zhong, Xing
Ma, Li-Xin
author_sort Hu, Yun-Hong
collection PubMed
description Toll-like receptor (TLR) signaling pathways need to be tightly controlled to avoid excessive inflammation and unwanted damage to the host. Myeloid differentiation primary response gene 88 (MyD88) is a critical adaptor of TLR signaling. Here, we identified the speckle-type POZ protein (SPOP) as a MyD88-associated protein. SPOP was recruited to MyD88 following TLR4 activation. TLR4 activation also caused the translocation of SPOP from the nucleus to the cytoplasm. SPOP depletion promoted the aggregation of MyD88 and recruitment of the downstream signaling kinases IRAK4, IRAK1 and IRAK2. Consistently, overexpression of SPOP inhibited the TLR4-mediated activation of NF-κB and production of inflammatory cytokines, whereas SPOP depletion had the opposite effects. Furthermore, knockdown of SPOP increased MyD88 aggregation and inflammatory cytokine production upon TLR2, TLR7 and TLR9 activation. Our findings reveal a mechanism by which MyD88 is regulated and highlight a role for SPOP in limiting inflammatory responses.
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spelling pubmed-82454732021-07-20 SPOP negatively regulates Toll-like receptor-induced inflammation by disrupting MyD88 self-association Hu, Yun-Hong Wang, Yang Wang, Fei Dong, Yan-Ming Jiang, Wan-Ling Wang, Ya-Ping Zhong, Xing Ma, Li-Xin Cell Mol Immunol Article Toll-like receptor (TLR) signaling pathways need to be tightly controlled to avoid excessive inflammation and unwanted damage to the host. Myeloid differentiation primary response gene 88 (MyD88) is a critical adaptor of TLR signaling. Here, we identified the speckle-type POZ protein (SPOP) as a MyD88-associated protein. SPOP was recruited to MyD88 following TLR4 activation. TLR4 activation also caused the translocation of SPOP from the nucleus to the cytoplasm. SPOP depletion promoted the aggregation of MyD88 and recruitment of the downstream signaling kinases IRAK4, IRAK1 and IRAK2. Consistently, overexpression of SPOP inhibited the TLR4-mediated activation of NF-κB and production of inflammatory cytokines, whereas SPOP depletion had the opposite effects. Furthermore, knockdown of SPOP increased MyD88 aggregation and inflammatory cytokine production upon TLR2, TLR7 and TLR9 activation. Our findings reveal a mechanism by which MyD88 is regulated and highlight a role for SPOP in limiting inflammatory responses. Nature Publishing Group UK 2020-03-31 2021-07 /pmc/articles/PMC8245473/ /pubmed/32235916 http://dx.doi.org/10.1038/s41423-020-0411-1 Text en © The Author(s) 2020 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Hu, Yun-Hong
Wang, Yang
Wang, Fei
Dong, Yan-Ming
Jiang, Wan-Ling
Wang, Ya-Ping
Zhong, Xing
Ma, Li-Xin
SPOP negatively regulates Toll-like receptor-induced inflammation by disrupting MyD88 self-association
title SPOP negatively regulates Toll-like receptor-induced inflammation by disrupting MyD88 self-association
title_full SPOP negatively regulates Toll-like receptor-induced inflammation by disrupting MyD88 self-association
title_fullStr SPOP negatively regulates Toll-like receptor-induced inflammation by disrupting MyD88 self-association
title_full_unstemmed SPOP negatively regulates Toll-like receptor-induced inflammation by disrupting MyD88 self-association
title_short SPOP negatively regulates Toll-like receptor-induced inflammation by disrupting MyD88 self-association
title_sort spop negatively regulates toll-like receptor-induced inflammation by disrupting myd88 self-association
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245473/
https://www.ncbi.nlm.nih.gov/pubmed/32235916
http://dx.doi.org/10.1038/s41423-020-0411-1
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