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Isoprenylcysteine Carboxyl Methyltransferase and Its Substrate Ras Are Critical Players Regulating TLR-Mediated Inflammatory Responses

In this study, we investigated the functional role of isoprenylcysteine carboxyl methyltransferase (ICMT) and its methylatable substrate Ras in Toll-like receptor (TLR)-activated macrophages and in mouse inflammatory disease conditions. ICMT and RAS expressions were strongly increased in macrophages...

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Autores principales: Yang, Woo Seok, Kim, Han Gyung, Kim, Eunji, Han, Sang Yun, Aziz, Nur, Yi, Young-Su, Kim, Sunggyu, Lee, Yunmi, Yoo, Byong Chul, Han, Jeung-Whan, Parameswaran, Narayanan, Kim, Ji Hye, Cho, Jae Youl
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291029/
https://www.ncbi.nlm.nih.gov/pubmed/32422978
http://dx.doi.org/10.3390/cells9051216
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author Yang, Woo Seok
Kim, Han Gyung
Kim, Eunji
Han, Sang Yun
Aziz, Nur
Yi, Young-Su
Kim, Sunggyu
Lee, Yunmi
Yoo, Byong Chul
Han, Jeung-Whan
Parameswaran, Narayanan
Kim, Ji Hye
Cho, Jae Youl
author_facet Yang, Woo Seok
Kim, Han Gyung
Kim, Eunji
Han, Sang Yun
Aziz, Nur
Yi, Young-Su
Kim, Sunggyu
Lee, Yunmi
Yoo, Byong Chul
Han, Jeung-Whan
Parameswaran, Narayanan
Kim, Ji Hye
Cho, Jae Youl
author_sort Yang, Woo Seok
collection PubMed
description In this study, we investigated the functional role of isoprenylcysteine carboxyl methyltransferase (ICMT) and its methylatable substrate Ras in Toll-like receptor (TLR)-activated macrophages and in mouse inflammatory disease conditions. ICMT and RAS expressions were strongly increased in macrophages under the activation conditions of TLRs by lipopolysaccharide (LPS, a TLR4 ligand), pam3CSK (TLR2), or poly(I:C) (TLR3) and in the colons, stomachs, and livers of mice with colitis, gastritis, and hepatitis. The inhibition and activation of ICMT and Ras through genetic and pharmacological approaches significantly affected the activation of interleukin-1 receptor-associated kinase (IRAK)s, tumor necrosis factor receptor associated factor 6 (TRAF6), transforming growth factor-β-activated kinase 1 (TAK1), mitogen-activated protein kinase (MAPK), and MAPK kinases (MAPKKs); translocation of the AP-1 family; and the expressions of inflammation-related genes that depend on both MyD88 and TRIF. Interestingly, the Ras/ICMT-mediated inflammatory reaction critically depends on the TIR domains of myeloid differentiation primary response 88 (MyD88) and TIR-domain-containing adapter-inducing interferon-β (TRIF). Taken together, these results suggest that ICMT and its methylated Ras play important roles in the regulation of inflammatory responses through cooperation with the TIR domain of adaptor molecules.
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spelling pubmed-72910292020-06-17 Isoprenylcysteine Carboxyl Methyltransferase and Its Substrate Ras Are Critical Players Regulating TLR-Mediated Inflammatory Responses Yang, Woo Seok Kim, Han Gyung Kim, Eunji Han, Sang Yun Aziz, Nur Yi, Young-Su Kim, Sunggyu Lee, Yunmi Yoo, Byong Chul Han, Jeung-Whan Parameswaran, Narayanan Kim, Ji Hye Cho, Jae Youl Cells Article In this study, we investigated the functional role of isoprenylcysteine carboxyl methyltransferase (ICMT) and its methylatable substrate Ras in Toll-like receptor (TLR)-activated macrophages and in mouse inflammatory disease conditions. ICMT and RAS expressions were strongly increased in macrophages under the activation conditions of TLRs by lipopolysaccharide (LPS, a TLR4 ligand), pam3CSK (TLR2), or poly(I:C) (TLR3) and in the colons, stomachs, and livers of mice with colitis, gastritis, and hepatitis. The inhibition and activation of ICMT and Ras through genetic and pharmacological approaches significantly affected the activation of interleukin-1 receptor-associated kinase (IRAK)s, tumor necrosis factor receptor associated factor 6 (TRAF6), transforming growth factor-β-activated kinase 1 (TAK1), mitogen-activated protein kinase (MAPK), and MAPK kinases (MAPKKs); translocation of the AP-1 family; and the expressions of inflammation-related genes that depend on both MyD88 and TRIF. Interestingly, the Ras/ICMT-mediated inflammatory reaction critically depends on the TIR domains of myeloid differentiation primary response 88 (MyD88) and TIR-domain-containing adapter-inducing interferon-β (TRIF). Taken together, these results suggest that ICMT and its methylated Ras play important roles in the regulation of inflammatory responses through cooperation with the TIR domain of adaptor molecules. MDPI 2020-05-14 /pmc/articles/PMC7291029/ /pubmed/32422978 http://dx.doi.org/10.3390/cells9051216 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yang, Woo Seok
Kim, Han Gyung
Kim, Eunji
Han, Sang Yun
Aziz, Nur
Yi, Young-Su
Kim, Sunggyu
Lee, Yunmi
Yoo, Byong Chul
Han, Jeung-Whan
Parameswaran, Narayanan
Kim, Ji Hye
Cho, Jae Youl
Isoprenylcysteine Carboxyl Methyltransferase and Its Substrate Ras Are Critical Players Regulating TLR-Mediated Inflammatory Responses
title Isoprenylcysteine Carboxyl Methyltransferase and Its Substrate Ras Are Critical Players Regulating TLR-Mediated Inflammatory Responses
title_full Isoprenylcysteine Carboxyl Methyltransferase and Its Substrate Ras Are Critical Players Regulating TLR-Mediated Inflammatory Responses
title_fullStr Isoprenylcysteine Carboxyl Methyltransferase and Its Substrate Ras Are Critical Players Regulating TLR-Mediated Inflammatory Responses
title_full_unstemmed Isoprenylcysteine Carboxyl Methyltransferase and Its Substrate Ras Are Critical Players Regulating TLR-Mediated Inflammatory Responses
title_short Isoprenylcysteine Carboxyl Methyltransferase and Its Substrate Ras Are Critical Players Regulating TLR-Mediated Inflammatory Responses
title_sort isoprenylcysteine carboxyl methyltransferase and its substrate ras are critical players regulating tlr-mediated inflammatory responses
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291029/
https://www.ncbi.nlm.nih.gov/pubmed/32422978
http://dx.doi.org/10.3390/cells9051216
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