Keller Mariko Aoyagi, Huang Chun-Yang, Ivessa Andreas, Singh Sukhwinder, Romanienko Peter J, Nakamura Michinari
Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
Division of Cardiovascular Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, 112, Taiwan.
iScience. 2023 Mar 16;26(4):106409. doi: 10.1016/j.isci.2023.106409. eCollection 2023 Apr 21.
BCL-2-like protein 1 (BCL2L1) is a key component of cell survival and death mechanisms. Its dysregulation and altered ratio of splicing variants associate with pathologies. However, isoform-specific loss-of-function analysis of BCL2L1 remains unexplored. Here we show the functional impact of genetically inhibiting Bcl-x short-isoform (Bcl-xS) . Bcl-xS is expressed in most tissues with predominant expression in the spleen and blood cells in mice. Bcl-xS knockout (KO) mice show no overt abnormality until 3 months of age. Thereafter, KO mice develop cardiac hypertrophy with contractile dysfunction and splenomegaly by 6 months. Cardiac fibrosis significantly increases in KO, but the frequency of apoptosis is indistinguishable despite cardiomyopathy. The Akt/mTOR and JNK/cJun signaling are upregulated in male KO heart, and the JNK/cJun is activated with increased Bax expression in KO spleen. These results suggest that Bcl-xS may be dispensable for development but is essential for maintaining the homeostasis of multiple organs.
BCL-2样蛋白1（BCL2L1）是细胞存活和死亡机制的关键组成部分。其失调以及剪接变体比例的改变与多种病理状况相关。然而，BCL2L1亚型特异性功能丧失分析仍未得到探索。在此，我们展示了基因抑制Bcl-x短亚型（Bcl-xS）的功能影响。Bcl-xS在大多数组织中表达，在小鼠的脾脏和血细胞中表达尤为显著。Bcl-xS基因敲除（KO）小鼠在3个月龄前未表现出明显异常。此后，KO小鼠在6个月时出现心脏肥大并伴有收缩功能障碍以及脾肿大。KO小鼠的心脏纤维化显著增加，尽管存在心肌病，但细胞凋亡频率并无差异。雄性KO心脏中Akt/mTOR和JNK/cJun信号上调，KO脾脏中JNK/cJun激活且Bax表达增加。这些结果表明，Bcl-xS对于发育可能并非必需，但对于维持多个器官的稳态至关重要。
