MYD88 is the key signaling adaptor-protein for Toll-like and interleukin-1 receptors. A somatic L265P mutation within the Toll/interleukin-1 receptor (TIR) domain of MYD88 is found in 90% of Waldenström macroglobulinemia cases and in a significant subset of diffuse large B-cell lymphomas. MYD88-L265P strongly promotes NF-κB pathway activation, JAK-STAT signaling and lymphoma cell survival. Previous studies have identified other residues of the TIR-domain crucially involved in NF-κB activation, including serine 257 (S257), indicating a potentially important physiological role in the regulation of MYD88 activation. Here, we demonstrate that MYD88 S257 is phosphorylated in B-cell lymphoma cells and that this phosphorylation is required for optimal TLR-induced NF-κB activation. Furthermore, we demonstrate that a phosphomimetic MYD88-S257D mutant promotes MYD88 aggregation, IRAK1 phosphorylation, NF-κB activation and cell growth to a similar extent as the oncogenic L265P mutant. Lastly, we show that expression of MYD88-S257D can rescue cell growth upon silencing of endogenous MYD88-L265P expression in lymphoma cells addicted to oncogenic MYD88 signaling. Our data suggest that the L265P mutation promotes TIR domain homodimerization and NF-κB activation by copying the effect of MY88 phosphorylation at S257, thus providing novel insights into the molecular mechanism underlying the oncogenic activity of MYD88-L265P in B-cell malignancies.
MYD88是Toll样受体和白介素-1受体的关键信号衔接蛋白。在华氏巨球蛋白血症的90%病例以及相当一部分弥漫性大B细胞淋巴瘤中，发现MYD88的Toll/白介素-1受体结构域存在L265P体细胞突变。MYD88-L265P强烈促进NF-κB通路激活、JAK-STAT信号传导及淋巴瘤细胞存活。既往研究已鉴定出TIR结构域中其他对NF-κB激活至关重要的残基，包括丝氨酸257，表明其在MYD88激活调控中可能具有重要生理作用。本研究中，我们证实B细胞淋巴瘤细胞中MYD88 S257会发生磷酸化，且该磷酸化是TLR诱导的NF-κB最佳激活所必需的。此外，我们发现磷酸模拟突变体MYD88-S257D能促进MYD88聚集、IRAK1磷酸化、NF-κB激活和细胞生长，其作用程度与致癌性L265P突变体相当。最后，我们证明在依赖致癌性MYD88信号传导的淋巴瘤细胞中，表达MYD88-S257D能够在沉默内源性MYD88-L265P表达后挽救细胞生长。我们的数据表明，L265P突变通过模拟S257位点的MYD88磷酸化效应，促进TIR结构域同源二聚化及NF-κB激活，从而为理解MYD88-L265P在B细胞恶性肿瘤中致癌活性的分子机制提供了新见解。
肿瘤(癌症)患者之家