FKBP8 protects the heart from hemodynamic stress by preventing the accumulation of misfolded proteins and endoplasmic reticulum-associated apoptosis in mice.
FKBP8 protects the heart from hemodynamic stress by preventing the accumulation of misfolded proteins and endoplasmic reticulum-associated apoptosis in mice.
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DOI：
10.1016/j.yjmcc.2017.11.004
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发表时间：
2018-01
影响因子：
5
通讯作者：
Otsu K
中科院分区：
文献类型：
--
作者：
Misaka T;Murakawa T;Nishida K;Omori Y;Taneike M;Omiya S;Molenaar C;Uno Y;Yamaguchi O;Takeda J;Shah AM;Otsu K
心肌细胞中的蛋白质质量控制对于维持细胞稳态至关重要。受损细胞器（例如线粒体和错误折叠蛋白质）在心脏中的积累与心力衰竭有关。在鉴定新型线粒体特异性自噬受体的过程中，我们发现 FK506 结合蛋白 8 (FKBP8)，也称为 FKBP38，与酵母线粒体自噬受体（自噬相关蛋白 32）具有相似的结构特征。然而，FKBP8 的敲低对 HEK293 细胞或 H9c2 肌细胞的线粒体自噬没有影响。由于FKBP8在心脏中的作用尚未完全阐明，本研究的目的是确定FKBP8在心脏中的功能作用。生成了心脏特异性 FKBP8 缺陷 (Fkbp8−/−) 小鼠。 Fkbp8−/− 小鼠在基线条件下没有表现出心脏表型。 Fkbp8−/− 和对照野生型同窝小鼠 (Fkbp8+/+) 小鼠通过横向主动脉缩窄 (TAC) 承受压力超负荷。 TAC 后 1 周，Fkbp8−/− 小鼠表现出左心室功能障碍和心室扩张并伴有肺充血。在 TAC 操作的 Fkbp8−/− 心脏中，凋亡心肌细胞的数量显着增加，同时裂解的 caspase-12 和内质网 (ER) 应激标记物的蛋白质水平增加。 Caspase-12 抑制导致 FKBP8 敲低 H9c2 肌细胞中过氧化氢诱导的细胞凋亡减弱。免疫细胞学和免疫沉淀分析表明，FKBP8 定位于分离心肌细胞的 ER 和线粒体，与热休克蛋白 90 相互作用。此外，在 FKBP8 敲除的 H9c2 肌细胞中存在错误折叠蛋白聚集体的积累，并且在 TAC 操作的核周区域存在电子致密沉积物。 Fkbp8−/− 心。数据表明，FKBP8 通过抑制错误折叠蛋白的积累和 ER 相关细胞凋亡，对心脏中的血流动力学应激发挥保护作用。这项研究首次确定了 FKBP8 在心脏中的体内作用。产生了心脏特异性 FKBP8 缺陷小鼠。 FKBP8 在应对压力超负荷时发挥心脏保护作用。 FKBP8 通过内质网介导的途径具有抗凋亡功能。 FKBP8 可防止错误折叠蛋白质的积累。
Protein quality control in cardiomyocytes is crucial to maintain cellular homeostasis. The accumulation of damaged organelles, such as mitochondria and misfolded proteins in the heart is associated with heart failure. During the process to identify novel mitochondria-specific autophagy (mitophagy) receptors, we found FK506-binding protein 8 (FKBP8), also known as FKBP38, shares similar structural characteristics with a yeast mitophagy receptor, autophagy-related 32 protein. However, knockdown of FKBP8 had no effect on mitophagy in HEK293 cells or H9c2 myocytes. Since the role of FKBP8 in the heart has not been fully elucidated, the aim of this study is to determine the functional role of FKBP8 in the heart. Cardiac-specific FKBP8-deficient (Fkbp8−/−) mice were generated. Fkbp8−/− mice showed no cardiac phenotypes under baseline conditions. The Fkbp8−/− and control wild type littermates (Fkbp8+/+) mice were subjected to pressure overload by means of transverse aortic constriction (TAC). Fkbp8−/− mice showed left ventricular dysfunction and chamber dilatation with lung congestion 1 week after TAC. The number of apoptotic cardiomyocytes was dramatically elevated in TAC-operated Fkbp8−/− hearts, accompanied with an increase in protein levels of cleaved caspase-12 and endoplasmic reticulum (ER) stress markers. Caspase-12 inhibition resulted in the attenuation of hydrogen peroxide-induced apoptotic cell death in FKBP8 knockdown H9c2 myocytes. Immunocytological and immunoprecipitation analyses indicate that FKBP8 is localized to the ER and mitochondria in the isolated cardiomyocytes, interacting with heat shock protein 90. Furthermore, there was accumulation of misfolded protein aggregates in FKBP8 knockdown H9c2 myocytes and electron dense deposits in perinuclear region in TAC-operated Fkbp8−/− hearts. The data suggest that FKBP8 plays a protective role against hemodynamic stress in the heart mediated via inhibition of the accumulation of misfolded proteins and ER-associated apoptosis. This study is the first to identify the in vivo role of FKBP8 in the heart. Cardiac-specific FKBP8-deficient mice were generated. FKBP8 plays a cardio-protective role in response to pressure overload. FKBP8 has anti-apoptotic functions via endoplasmic reticulum-mediated pathway. FKBP8 prevents the accumulation of misfolded proteins.
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影响因子：
82.9
作者：
通讯作者：
--
影响因子：
64.8
作者：
Oka, Takafumi;Hikoso, Shungo;Yamaguchi, Osamu;Taneike, Manabu;Takeda, Toshihiro;Tamai, Takahito;Oyabu, Jota;Murakawa, Tomokazu;Nakayama, Hiroyuki;Nishida, Kazuhiko;Akira, Shizuo;Yamamoto, Akitsugu;Komuro, Issei;Otsu, Kinya
通讯作者：
Otsu, Kinya
影响因子：
7.7
作者：
Bhujabal, Zambarlal;Birgisdottir, Asa B.;Johansen, Terje
通讯作者：
Johansen, Terje
影响因子：
11.4
作者：
Edlich, F;Weiwad, M;Fischer, G
通讯作者：
Fischer, G
影响因子：
20.1
作者：
McLendon PM;Robbins J
通讯作者：
Robbins J