The E3 ubiquitin ligase HectD3 is a novel regulator of cardiac hypertrophy and inflammation

The HECT domain E3 ubiquitin protein ligase 3 (HectD3) is highly expressed in the heart, but its cardiac function is still unknown. Here, we identified SUMO2 and Stat1 as novel cardiac substrates for HectD3. SUMO2 is a potent inducer of Calcineurin-NFAT mediated cardiomyocyte hypertrophy, whereas, Stat1 is an interferon responsive transcription factor that plays crucial role in cellular immune responses. HectD3 overexpression on one hand attenuated SUMO2-Calcineurin-NFAT signaling driven cardiomyocyte hypertrophy, on the other hand, it abrogated the pro-inflammatory actions of LPS or interferon-γ in cardiomyocytes in vitro. Consistently, AAV9-mediated overexpression of HectD3 in mice in vivo not only reduced cardiac SUMO2/Stat1 levels and pathological hypertrophy but also alleviated macrophage infiltration and fibrosis induced by pressure overload. In conclusion, we describe a novel cardioprotective mechanism involving the ubiquitin ligase HectD3, which exerts anti-hypertrophic and anti-inflammatory effects via dual regulation of SUMO2 and Stat1.

HECT结构域E3泛素蛋白连接酶3（HectD3）在心脏中呈高表达，但目前其心脏功能仍未明确。本研究鉴定出小泛素样修饰蛋白2（SUMO2）与信号转导与转录激活因子1（Stat1）为HectD3的新型心脏底物。其中，SUMO2是钙调神经磷酸酶-活化T细胞核因子（Calcineurin-NFAT）介导的心肌肥大的强效诱导因子；而Stat1作为干扰素应答转录因子，在细胞免疫应答中发挥关键调控作用。体外实验中，过表达HectD3一方面可减弱SUMO2-钙调神经磷酸酶-活化T细胞核因子信号通路驱动的心肌肥大，另一方面可阻断脂多糖（LPS）或干扰素γ（interferon-γ）诱导的心肌细胞促炎效应。体内实验结果与之一致，通过腺相关病毒9型（AAV9）介导小鼠心脏过表达HectD3，不仅可降低心脏内SUMO2与Stat1的蛋白水平、减轻病理性心肌肥大，还可缓解压力超负荷诱导的巨噬细胞浸润与心肌纤维化。综上，本研究揭示了一条由泛素连接酶HectD3介导的新型心脏保护机制，该机制通过双重调控SUMO2与Stat1发挥抗肥大与抗炎效应。