Department of Basic Medical Morphology, Medical College, Xijing University, Xi'an, China.
Department of Basic Functioning Medicine, Medical College, Xijing University, Xi'an, China.
Aging Cell. 2020 Oct;19(10):e13217. doi: 10.1111/acel.13217. Epub 2020 Aug 9.
Increased oxidative stress is well known to cause testicular dysfunction in aging males, but the detailed relationships between aging, oxidative stress, and testicular function remain to be elucidated. LIM and cysteine-rich domains 1 (LMCD1) regulates fundamentally cellular process by interacting with transcription factors. A recent study has identified Lmcd1 as one of the most upregulated nuclear proteins associated with Sertoli cell (SC) differentiation, raising the possibility that testicular actions of LMCD1 are likely to take place. Herein, we reported that LMCD1 was exclusively expressed in the nuclei of SCs. This expression was regulated by TNF-α signaling produced by apoptotic germ cells (GCs) and was suppressed by oxidative stress in a STAT3-dependent manner. Ablation of endogenous LMCD1 expression caused lipid accumulation and senescence in GC co-incubated SCs. Using a previously validated in vivo siRNA approach, we showed that LMCD1 depletion significantly impaired male fertility by inducing oligozoospermia and asthenospermia. Mechanistically, LMCD1 upregulation was associated with the nuclear enrichment of the nuclear factor of activated T cells 1 (NFAT1), a core component of Ca /calmodulin-dependent pathway. LMCD1 facilitated the dephosphorylation and nuclear translocation of NFAT1, which consequently expedited the transactivation of Txlna, a binding partner of the syntaxin family essential for testicular phagocytosis, and thus promoted the removal of apoptotic GCs by phagocytic SCs. Collectively, LMCD1 may operate as a novel pretranscriptional integrator linking SC phagocytosis, lipid homeostasis, and cell senescence.
氧化应激增加众所周知会导致衰老雄性的睾丸功能障碍，但衰老、氧化应激和睾丸功能之间的详细关系仍有待阐明。LIM 和富含半胱氨酸结构域 1（LMCD1）通过与转录因子相互作用来调节基本的细胞过程。最近的一项研究已经确定 Lmcd1 是与支持细胞（SC）分化相关的上调核蛋白之一，这使得 LMCD1 可能在睾丸中发挥作用。在此，我们报告称，LMCD1 仅在 SC 的核中表达。这种表达受凋亡生殖细胞（GC）产生的 TNF-α信号的调节，并以 STAT3 依赖的方式被氧化应激抑制。内源性 LMCD1 表达的缺失导致与 GC 共孵育的 SC 中脂质积累和衰老。使用以前验证的体内 siRNA 方法，我们表明 LMCD1 的耗竭通过诱导少精子症和弱精子症显著损害男性生育能力。在机制上，LMCD1 的上调与激活 T 细胞核因子 1（NFAT1）的核富集有关，NFAT1 是 Ca/钙调蛋白依赖性途径的核心组成部分。LMCD1 促进 NFAT1 的去磷酸化和核易位，从而加速结合蛋白 Txlna 的转录激活，该蛋白对于睾丸吞噬作用至关重要，并且促进吞噬性 SC 去除凋亡的 GC。总的来说，LMCD1 可能作为一种新型的转录前整合因子，连接 SC 吞噬作用、脂质稳态和细胞衰老。
