Testicular Lmcd1 regulates phagocytosis by Sertoli cells through modulation of NFAT1/Txlna signaling pathway.
Testicular Lmcd1 regulates phagocytosis by Sertoli cells through modulation of NFAT1/Txlna signaling pathway.
复制标题
睾丸Lmcd1通过调节NFAT1/Txlna信号通路调节支持细胞的吞噬作用
作者：
Jin X;Zhang S;Ding T;Zhao P;Zhang C;Zhang Y;Li W
众所周知，氧化应激增加会导致老年男性睾丸功能障碍，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和富含半胱氨酸的结构域1（LMCD 1）通过与转录因子相互作用从根本上调节细胞过程。最近的一项研究已经确定Lmcd 1是与支持细胞（SC）分化相关的最上调的核蛋白之一，提高了Lmcd 1的睾丸作用可能发生的可能性。在此，我们报道了LMCD 1只在SC的细胞核中表达。这种表达受到凋亡生殖细胞（GC）产生的TNF-α信号的调节，并以STAT 3依赖性方式受到氧化应激的抑制。内源性LMCD 1表达的消融导致GC共孵育的SC中的脂质积聚和衰老。使用先前验证的体内siRNA方法，我们表明LMCD 1缺失通过诱导少精子症和弱精子症显著损害男性生育力。从机制上讲，LMCD 1上调与活化T细胞核因子1（NFAT 1）的核富集相关，NFAT 1是Ca 2 +/钙调蛋白依赖性途径的核心组分。LMCD 1促进NFAT 1的去磷酸化和核转位，从而加速Txlna的反式激活，Txlna是睾丸吞噬作用所必需的突触融合蛋白家族的结合伴侣，从而促进吞噬SC清除凋亡的GC。总的来说，LMCD 1可以作为一种新的转录前整合剂，连接SC吞噬作用，脂质稳态和细胞衰老。衰老睾丸中SC特异性LMCD 1表达受到氧化应激的影响LMCD 1通过调节NFAT 1/Txlna信号通路调节支持细胞的吞噬作用。
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 Ca2+/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. SCs‐specific LMCD1 expression is compromised by oxidative stress in aged testis. LMCD1 regulates phagocytosis by Sertoli cells through modulation of NFAT1/Txlna signaling pathway.
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影响因子：
3.7
作者：
Li W;Zhu S;Li J;Huang Y;Zhou R;Fan X;Yang H;Gong X;Eissa NT;Jahnen-Dechent W;Wang P;Tracey KJ;Sama AE;Wang H
通讯作者：
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2.9
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通讯作者：
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影响因子：
4.1
作者：
Delfino, FJ;Boustead, JN;Walker, WH
通讯作者：
Walker, WH
影响因子：
4
作者：
Du L;Yamamoto S;Burnette BL;Huang D;Gao K;Jamshidi N;Kuo MD
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影响因子：
3.7
作者：
Ma L;Li W;Zhu HP;Li Z;Sun ZJ;Liu XP;Zhao J;Zhang JS;Zhang YQ
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Zhang YQ