HIPK2 phosphorylates HDAC3 for NF-κB acetylation to ameliorate colitis-associated colorectal carcinoma and sepsis
HIPK2 phosphorylates HDAC3 for NF-κB acetylation to ameliorate colitis-associated colorectal carcinoma and sepsis
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HIPK2 磷酸化 HDAC3 进行 NF-kappa B 乙酰化，以改善结肠炎相关结直肠癌和脓毒症
DOI：
10.1073/pnas.2021798118
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发表时间：
2021-07-13
影响因子：
11.1
通讯作者：
Wei, Bin
中科院分区：
文献类型：
--
作者：
Zhang, Fang;Qi, Linlin;Wei, Bin
虽然炎症对于病原体的清除至关重要，但不受控制的炎症也有助于多种疾病的发展，如癌症和败血症。由于核内NF-κ B介导的反式激活是诱导炎症的各种刺激的关键下游，因此寻找特异性调节NF-κ B激活的核定位靶点将提供重要的治疗应用。在这里，我们已经确定，同源结构域相互作用蛋白激酶2（HIPK 2），核丝氨酸/苏氨酸激酶，增加其在炎症巨噬细胞的表达。重要的是，HIPK 2缺陷或过表达可分别增强或抑制LPS刺激的巨噬细胞中的炎症反应。HIPK 2缺陷型小鼠对LPS诱导的内毒素血症和CLP诱导的脓毒症更敏感。Hipk（2+/-）骨髓细胞（BM）的连续转移也加重AOM/DSS诱导的结直肠癌。在机制上，HIPK 2结合并磷酸化组蛋白脱乙酰酶3（HDAC 3）的丝氨酸374以抑制其酶活性，从而减少p65在赖氨酸218处的脱乙酰化以抑制NF-κ B活化。值得注意的是，HDAC 3抑制剂保护野生型或Hipk 2（-/-）BM重建小鼠免受LPS诱导的内毒素血症。我们的研究结果表明，巨噬细胞中的HIPK 2 HDAC 3-p65模块抑制了过度炎症，这可能代表了结肠炎相关结肠直肠癌和脓毒症的新的治疗机制。
Although inflammation is critical for the clearance of pathogens, uncontrolled inflammation also contributes to the development of multiple diseases such as cancer and sepsis. Since NF-kappa B-mediated transactivation in the nucleus is pivotal downstream of various stimuli to induce inflammation, searching the nuclear-localized targets specifically regulating NF-kappa B activation will provide important therapeutic application. Here, we have identified that homeodomaininteracting protein kinase 2 (HIPK2), a nuclear serine/threonine kinase, increases its expression in inflammatory macrophages. Importantly, HIPK2 deficiency or overexpression could enhance or inhibit inflammatory responses in LPS-stimulated macrophages, respectively. HIPK2-deficient mice were more susceptible to LPSinduced endotoxemia and CLP-induced sepsis. Adoptive transfer of Hipk(2+/-) bone marrow cells (BMs) also aggravated AOM/DSS-induced colorectal cancer. Mechanistically, HIPK2 bound and phosphorylated histone deacetylase 3 (HDAC3) at serine 374 to inhibit its enzymatic activity, thus reducing the deacetylation of p65 at lysine 218 to suppress NF-kappa B activation. Notably, the HDAC3 inhibitors protected wild-type or Hipk2(-/-) BMs-reconstituted mice from LPS-induced endotoxemia. Our findings suggest that the HIPK2HDAC3-p65 module in macrophages restrains excessive inflammation, which may represent a new layer of therapeutic mechanism for colitis-associated colorectal cancer and sepsis.