MYD88

Official Full Name

MYD88 innate immune signal transduction adaptor

Organism

Homo sapiens

GeneID

4615

Background

This gene encodes a cytosolic adapter protein that plays a central role in the innate and adaptive immune response. This protein functions as an essential signal transducer in the interleukin-1 and Toll-like receptor signaling pathways. These pathways regulate that activation of numerous proinflammatory genes. The encoded protein consists of an N-terminal death domain and a C-terminal Toll-interleukin1 receptor domain. Patients with defects in this gene have an increased susceptibility to pyogenic bacterial infections. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2010]

Synonyms

WM1; IMD68; MYD88D;

Protein Sequence

MAAGGPGAGSAAPVSSTSSLPLAALNMRVRRRLSLFLNVRTQVAADWTALAEEMDFEYLEIRQLETQADPTGRLLDAWQGRPGASVGRLLELLTKLGRDDVLLELGPSIEEDCQKYILKQQQEEAEKPLQVAAVDSSVPRTAELAGITTLDDPLGHMPERFDAFICYCPSDIQFVQEMIRQLEQTNYRLKLCVSDRDVLPGTCVWSIASELIEKRCRRMVVVVSDDYLQSKECDFQTKFALSLSPGAHQKRLIPIKYKAMKKEFPSILRFITVCDYTNPCTKSWFWTRLAKALSLP

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Detailed Information

Myeloid differentiation factor 88 (MyD88) is the first adaptor protein found in the Toll-like receptor (TLR) signaling pathway. In 1990, LORD et al. discovered the MyD88 gene when mouse M1 cells differentiated into macrophages, and found that MyD88 RNA was enriched in mouse bone marrow rather than in non-bone marrow tissue. Therefore, MyD88 is considered to be a marker of myeloid differentiation factor. Later, it was found that MyD88 is also expressed in non-myeloid tissues, mainly expressed in immune cells, such as monocyte lineage, thymocyte lineage, T lymphocyte lineage, B lymphocyte lineage, Th1 cell line and Th2 cell line.

In the molecular structure of MyD88, the C-terminus contains a TIR domain that interacts with the TIR domain on the TLR; its N-terminus is similar to the death domain and interacts with other proteins with death domains. The death domain of MyD88 is associated with TLR-mediated apoptosis. MyD88 also has a mediating domain that interacts with interleukin-1 receptorassociated kinase (IRAK) to activate downstream proinflammatory cytokines in the TLR signaling pathway. As an important adaptor protein, MyD88 was first recruited after TLR activation, mediating downstream signaling, which is a key link in TLR signaling.

Figure 1. Signal transduction downstream of MYD88-dependent and independent pathways. (Wang, J. Q., et al. 2014)

MyD88 and Breast Cancer

In clinical case studies, MyD88 was highly expressed in adjacent tissues, strongly expressed in tumor cells, and weakly expressed in normal tissues surrounding breast cancer, suggesting differential expression of MyD88 in different types of cells and breast tumors. Diameter, lymphatic invasion and metastasis are closely related. PARK et al. proposed that lipopolysaccharide (LPS) is present in tumor cells and induces tumor invasion and metastasis, and LPS can up-regulate the expression of leukotriene B4 receptor 2 (BLT2R), thereby promoting MDA- Invasion of MB-231 and MDA-MB-435 breast cancer cells. Overexpression of MyD88 induces increased synthesis of IL-6 and IL-8, up-regulates BLT2 mRNA expression, and increases invasion of MDA-MB-231 cells. Therefore, LPS enhances breast cancer cell invasion and metastasis via the “MyD88-BLT2” signaling cascade. In the study of disease free surviving (DFS) and overall survival (OS) in patients with invasive ductal carcinoma (IDC), the expression of MyD88 and TLR4 was positively related with tumor metastasis. Patients with high expression are more likely to have metastasis and death, while patients with low expression have higher DFS and OS than patients with high expression. In a multivariate analysis, high DFD expression was independently associated with a poor prognosis for breast cancer in patients with reduced DFS and OS.

MyD88 and Clinical Treatment

The relationship between the function and disease of MyD88 is gradually being emphasized and becoming the target of drug-targeted therapeutic research. The MyD88-dependent pathway is considered to be a new target and strategy for disease intervention. The TLR/MyD88 signal pathway is an important driver of inflammation and cancer and is a possible target for anti-tumor therapy. The researchers used the DIR domain homodimer of MyD88 as a target to synthesize a series of compounds (such as TJ-M2010-5, EM-163, T923, ST2825, etc.). Studies have shown that inhibition of the autodimerization of MyD88 by tj-m2010-5 inhibits the expression of downstream inflammatory cytokines and chemokines (tnf-alpha, il-6, g-csf, mip-1 beta, TGF beta 1, il-11, il-17a, il-22, and il-23) and the infiltration of immune cells (macrophages, dendritic cells, neutrophils, and mouse colonic CD4+ T cells), which is expected to become colon treatment for inflammation or colitis associated cancer (CAC).

References:

TIAN T，SUN D，WANG P，et a l. (2015). Roles of toll-like receptor 7 and 8 in prevention of intrauterine transmission of hepatitis b virus. Cellular Physiology and Biochemistry, 37(2), 445-453.
Park, G. S. , & Kim, J. H. . (2015). Myeloid differentiation primary response gene 88-leukotriene b4 receptor 2 cascade mediates lipopolysaccharide-potentiated invasiveness of breast cancer cells. Oncotarget, 6(8), 5749-59.
Wang, J. Q. , Jeelall, Y. S. , & Ferguson, L. L. . (2014). Toll-like receptors and cancer: myd88 mutation and inflammation. Frontiers in Immunology, 5(367), 367.

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