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

Woo Seok Yang,Han Gyung Kim,Ji Hye Kim,Sunggyu Kim,Young-Su Yi,Eunji Kim,Sang Yun Han,Yunmi Lee,Jeung-Whan Han,Jae Youl Cho,Byong Chul Yoo,Nur Aziz,Narayanan Parameswaran

doi:10.3390/cells9051216

Abstract

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.

Highlights

Macrophages are innate immune cells involved in homeostatic and pathophysiological processes, including the development of inflammatory diseases
We focus on understanding the functional involvement of isoprenylcysteine carboxyl methyltransferase (ICMT) and rat sarcoma (Ras) in inflammatory responses, including intracellular signaling, inflammatory gene expression, and pathophysiological symptoms mediated by Toll-like receptor (TLR) and their adaptor molecules, such as
Those effects were observed in RAW264.7 cells; ICMT mRNA and ICMT protein levels were found to be increased in cancerous macrophages (Figure 1B)

Summary

Introduction

Macrophages are innate immune cells involved in homeostatic and pathophysiological processes, including the development of inflammatory diseases. Cells 2020, 9, 1216 receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) presented by microbes or damage-associated molecular patterns (DAMPs) released from damaged cells. Activation of macrophage PRRs by PAMPs and DAMPs is known to be an important factor in the pathogenesis of inflammatory diseases. A representative family of PRRs is Toll-like receptors (TLRs), which are type I transmembrane proteins [1,2]. The activation of TLRs by various ligands and DAMPs initiates inflammatory signaling cascades via adaptor molecules such as myeloid differentiation factor 88. (MyD88) and Toll-interleukin (IL)-1 receptor domain–containing adaptor molecule-1 (TRIF) [3,4]. MyD88 and TRIF have structurally identical domains, including the Toll/IL-1R (TIR) domain

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Conclusion