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

被引：8
作者：
Samba-Mondonga, Macha [1 ,2 ]
Calve, Annie [1 ]
Mallette, Frederick A. [2 ,3 ]
Santos, Manuela M. [1 ,2 ]
机构：
[1] Univ Montreal CRCHUM, Nutr & Microbiome Lab, Ctr Rech, Ctr Hosp, Montreal, PQ, Canada
[2] Univ Montreal, Dept Med, Montreal, PQ, Canada
[3] Univ Montreal, Ctr Rech, Hop Maisonneuve Rosemont, Montreal, PQ, Canada
来源：
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY | 2018年 / 6卷
基金：
加拿大自然科学与工程研究理事会; 加拿大健康研究院;
关键词：
MyD88; BMP6; SMAD4; iron; hepcidin; L265P mutation; SMAD6; Waldenstrom's macroglobulinemia; BONE MORPHOGENETIC PROTEIN; ADAPTER PROTEIN; UP-REGULATION; TIR DOMAIN; ACTIVIN B; INDUCTION; HEPATOCYTES; SMAD1/5/8; GROWTH; BMP6;
D O I：
10.3389/fcell.2018.00105
中图分类号：
Q2 [细胞生物学];
学科分类号：
071009 ; 090102 ;
摘要：
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 Waldenstrom'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.
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页数：13
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