Tax1 banding protein 1 (Tax1bp1) was originally identified as an NF-κB regulatory protein that participated in inflammatory, antiviral and innate immune processes. Tax1bp1 also functions as an autophagy receptor that plays a role in autophagy. Our previous study shows that Tax1bp1 protects against cardiomyopathy in STZ-induced diabetic mice. In this study we investigated the role of Tax1bp1 in heart failure. Pressure overload-induced heart failure model was established in mice by aortic banding (AB) surgery, and angiotensin II (Ang II)-induced heart failure model was established by infusion of Ang II through osmotic minipump for 4 weeks. We showed that the expression levels of Tax1bp1 in the heart were markedly increased 2 and 4 weeks after AB surgery. Knockdown of Tax1bp1 in mouse hearts significantly ameliorated both AB- and Ang II infusion-induced heart failure parameters. On the contrary, AB-induced heart failure was aggravated in cardiac-specific Tax1bp1 transgenic mice. Similar results were observed in neonatal rat cardiomyocytes (NRCMs) under Ang II insult. We demonstrated that the pro-heart failure effect of Tax1bp1 resulted from its interaction with the E3 ligase ITCH to promote the transcription factor P73 ubiquitination and degradation, causing enhanced BCL2 interacting protein 3 (BNIP3)-mediated cardiomyocyte apoptosis. Knockdown ITCH or BNIP3 in NRCMs significantly reduced Ang II-induced apoptosis in vitro. Similarly, BNIP3 knockdown attenuated heart failure in cardiac-specific Tax1bp1 transgenic mice. In the left ventricles of heart failure patients, Tax1bp1 expression level was significantly increased; Tax1bp1 gene expression was negatively correlated with left ventricular ejection fraction in heart failure patients. Collectively, the Tax1bp1 increase in heart failure enhances ITCH-P73-BNIP3-mediated cardiomyocyte apoptosis and induced cardiac injury. Tax1bp1 may serve as a potent therapeutic target for the treatment of heart failure.

• Cardiac Tax1bp1 transgene mice were more vulnerable to cardiac dysfunction under stress.

• Cardiac Tax1bp1 transgene mice were more vulnerable to cardiac dysfunction under stress.

• Knockout of Tax1bp1 in mouse hearts ameliorated heart failure induced by pressure overload.

• Tax1bp1 interacts with the E3 ligase Itch to promote P73 ubiquitination and degradation, causing enhanced BNIP3-mediated apoptosis.

• Tax1bp1 may become a target of new therapeutic methods for treating heart failure.

Tax1 带带蛋白 1 (Tax1bp1) 最初被鉴定为一种 NF-κB 调节蛋白，参与炎症、抗病毒和先天免疫过程。Tax1bp1 还作为自噬受体在自噬中发挥作用。我们之前的研究表明，Tax1bp1 可以预防 STZ 诱导的糖尿病小鼠的心肌病。在这项研究中，我们调查了 Tax1bp1 在心力衰竭中的作用。通过主动脉结扎（AB）手术建立小鼠压力超载诱发心力衰竭模型，通过微型渗透泵输注Ang II 4周建立血管紧张素II（Ang II）诱发心力衰竭模型。我们发现，AB 手术后 2 周和 4 周，心脏中 Tax1bp1 的表达水平显着增加。小鼠心脏中 Tax1bp1 的敲除显着改善了 AB 和 Ang II 输注引起的心力衰竭参数。相反，在心脏特异性Tax1bp1转基因小鼠中，AB诱导的心力衰竭加重。在 Ang II 损伤下的新生大鼠心肌细胞 (NRCM) 中观察到类似的结果。我们证明，Tax1bp1 的促心力衰竭作用是由于其与 E3 连接酶 ITCH 相互作用，促进转录因子 P73 泛素化和降解，从而增强 BCL2 相互作用蛋白 3 (BNIP3) 介导的心肌细胞凋亡。NRCM 中的 ITCH 或 BNIP3 敲低可显着减少体外 Ang II 诱导的细胞凋亡。同样，BNIP3 敲低可减轻心脏特异性 Tax1bp1 转基因小鼠的心力衰竭。心力衰竭患者左心室中，Tax1bp1表达水平显着升高；心力衰竭患者中 Tax1bp1 基因表达与左心室射血分数呈负相关。总的来说，心力衰竭中 Tax1bp1 的增加会增强 ITCH-P73-BNIP3 介导的心肌细胞凋亡并诱导心脏损伤。Tax1bp1可能作为治疗心力衰竭的有效治疗靶点。

• Cardiac Tax1bp1 转基因小鼠在压力下更容易出现心脏功能障碍。

• Cardiac Tax1bp1 转基因小鼠在压力下更容易出现心脏功能障碍。

• 敲除小鼠心脏中的Tax1bp1 可改善压力超负荷引起的心力衰竭。

• Tax1bp1 与E3 连接酶Itch 相互作用，促进P73 泛素化和降解，从而增强BNIP3 介导的细胞凋亡。

• Tax1bp1 可能成为治疗心力衰竭的新治疗方法的靶点。