The interleukin-1 receptor-activated kinase 4 (IRAK4) belongs to the IRAK family of serine/threonine kinases and plays a central role in the innate immune response. However, the function of IRAK4 in tumor growth and progression remains elusive. Here we sought to determine the enzymatic and scaffolding functions of IRAK4 in activated B-cell-like diffuse large B cell lymphoma (ABC DLBCL). We chose a highly selective IRAK4 kinase inhibitor to probe the biological effects of kinase inhibition and developed a series of IRAK4 degraders to evaluate the effects of protein degradation in ABC DLBCL cells. Interestingly, the results demonstrated that neither IRAK4 kinase inhibition nor protein degradation led to cell death or growth inhibition, suggesting a redundant role for IRAK4 in ABC DLBCL cell survival. IRAK4 degraders characterized in this study provide useful tools for understanding IRAK4 protein scaffolding function, which was previously unachievable using pharmacological perturbation.

白介素1受体激活的激酶4（IRAK4）属于丝氨酸/苏氨酸激酶的IRAK家族，在先天免疫应答中起着核心作用。然而，IRAK4在肿瘤生长和进展中的功能仍然难以捉摸。在这里，我们试图确定IRAK4在活化的B细胞样弥漫性大B细胞淋巴瘤（ABC DLBCL）中的酶促和支架功能。我们选择了高度选择性的IRAK4激酶抑制剂来探测激酶抑制的生物学效应，并开发了一系列IRAK4降解剂来评估ABC DLBCL细胞中蛋白质降解的作用。有趣的是，结果表明IRAK4激酶的抑制作用和蛋白质降解都不会导致细胞死亡或生长抑制，这表明IRAK4在ABC DLBCL细胞存活中具有多余的作用。