MyD88 Regulates the Expression of SMAD4 and the Iron Regulatory Hormone Hepcidin

Abstract

The myeloid differentiation primary response gene 88 (MyD88) is an adaptive protein that is essential for the induction of inflammatory cytokines through almost all the Toll-like receptors (TLRs). TLRs recognize molecular patterns present in microorganisms called pathogen-associated molecular patterns. Therefore, MyD88 plays an important role in innate immunity since its activation triggers the first line of defense against microorganisms. Herein, we describe the first reported role of MyD88 in an interconnection between innate immunity and the iron-sensing pathway (BMP/SMAD4). We found that direct interaction of MyD88 with SMAD4 protein activated hepcidin expression. The iron regulatory hormone hepcidin is indispensable for the intestinal regulation of iron absorption and iron recycling by macrophages. We show that MyD88 induces hepcidin expression in a manner dependent on the proximal BMP responsive element on the hepcidin gene (HAMP) promoter. We identified the Toll/interleukin-1 receptor (TIR) domain of MyD88 as the domain of interaction with SMAD4. Furthermore, we show that BMP6 stimulation, which activates SMAD6 expression, also induces MyD88 proteosomal degradation as a negative feedback mechanism to limit hepcidin induction. Finally, we report that the MyD88 gain-of-function L265P mutation, frequently encountered in B-cell lymphomas such as Waldenström’s macroglobulinemia, enhances hepcidin expression and iron accumulation in B cell lines. Our results reveal a new potential role for MyD88 in the SMAD signaling pathway and iron homeostasis regulation.

Renoprotective Effects of Maslinic Acid on Experimental Renal Fibrosis in Unilateral Ureteral Obstruction Model via Targeting MyD88

“…Moreover, TGF-β induced nuclear activation of Smad4 in NRK49F cells was significantly downregulated by transfection of siRNA targeting MyD88. These findings are consistent with recent study demonstrating that MyD88 expression levels affect Smad4 protein levels in Hub7 hepatoma cells through the Toll/IL-1 receptor domain of the MyD88 protein ( Samba-Mondonga et al, 2018 ). Taken together with the present study, MA exerts its anti-fibrotic effects on the TGF-β/Smad pathway via targeting MyD88.…”

“…In a previous study, MyD88 was shown to be directly upstream of the Smad4 signaling cascade ( Samba-Mondonga et al, 2018 ). To evaluate the effect of MyD88 on the TGF-β/Smad signaling pathway, we examined the effect of MyD88 knockdown on Smad4 expression in NRK49F cells.…”

β-Elemene Attenuates Renal Fibrosis in the Unilateral Ureteral Obstruction Model by Inhibition of STAT3 and Smad3 Signaling via Suppressing MyD88 Expression

“…Signal crosstalk between MyD88 and the Smad family has been reported involving Smad4 and Smad6, etc. [ 53 , 54 ], but there are few studies on whether there is an association between MyD88 and Smad3 [ 55 ]. In the present study, β-elemene significantly inhibited MyD88 expression in UUO mice, and TGF-β stimulated NRK49F cells.…”

Identification of a Candidate Gene Set Signature for the Risk of Progression in IgM MGUS to Smoldering/Symptomatic Waldenström Macroglobulinemia (WM) by a Comparative Transcriptome Analysis of B Cells and Plasma Cells

“…A previous study described the relationship between MYD88 and SMADs genes in WM. Indeed, the MYD88 protein directly interacts with SMAD6 which negatively regulates the TGF-β family signaling pathway [ 60 ].…”