Inactivation of glycogen synthase kinase-3α is required for mitochondria-mediated apoptotic germ cell phagocytosis in Sertoli cells.
Inactivation of glycogen synthase kinase-3α is required for mitochondria-mediated apoptotic germ cell phagocytosis in Sertoli cells.
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DOI：
10.18632/aging.101614
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发表时间：
2018-11-06
期刊：
影响因子：
--
通讯作者：
He B
中科院分区：
文献类型：
--
作者：
Gong Y;Zhang Z;Chang Z;Zhou H;Zhao R;He B
支持细胞（SC）快速有效地清除凋亡的生殖细胞（GC）对精子发生具有重要意义。吞噬细胞中的高线粒体活性对于持续清除凋亡细胞至关重要。然而，对潜在的分子机制知之甚少。糖原合成酶激酶-3 α（Glycogen synthase kinase-3α，GSK 3 α）是一种参与线粒体活性调节的蛋白激酶。免疫组化结果显示，SC中主要存在Ser 21磷酸化GSK 3 α（失活）信号。热休克诱导的GCs凋亡和SC中GSK 3 α的去磷酸化是研究GSK 3 α在吞噬作用中的作用的理想模型。GSK 3 α抑制剂预处理的HS小鼠的凋亡GC数量显著低于正常对照组。体外吞噬实验表明，GSK 3 α激活的SC的吞噬活性下调，而补充GSK 3 α抑制剂可恢复这一过程。此外，GSK 3 α的活化还参与了线粒体超微结构和活性的改变。特别是，GSK 3 α激活通过发动蛋白相关蛋白1在Ser 637的磷酸化抑制线粒体分裂。线粒体活性的改变导致了SC内脂滴的积累和代谢模式的改变。总之，我们的研究结果表明，GSK 3 α的失活是必需的，在SC中，GSK 3 α介导的凋亡GC吞噬。
The rapid and efficient clearance of apoptotic germ cells (GCs) by Sertoli cells (SCs) is important for spermatogenesis. High mitochondrial activity in phagocytes is critical for continued clearance of apoptotic cells. However, the underlying molecular mechanism is poorly understood. Glycogen synthase kinase-3α (GSK3α) is a protein kinase that participates in the regulation of mitochondrial activity. Immunohistochemistry evidenced the predominant presence of the Ser21 phosphorylation GSK3α (inactivation) signal in SCs. Heat shock-induced apoptosis of GCs and dephosphorylation of GSK3α in SCs is a perfect model to investigate the role of GSK3α in phagocytic action. The number of apoptotic GCs was significantly lower in GSK3α inhibitor pre-treated mice with HS compared to normal control. In vitro phagocytosis assays shown that the phagocytic activity in GSK3α activated SCs was downregulated, while GSK3α inhibitor supplementation restored this process. Moreover, GSK3α activation participates in the alteration of the mitochondrial ultrastructure and activity. In particular, GSK3α activation inhibits mitochondrial fission via phosphorylation of dynamin related protein 1 at Ser637. Changes of mitochondrial activity resulted in the accumulation of lipid droplets and the alteration of metabolism pattern in SCs. In summary, our results demonstrate that inactivation of GSK3α is required for mitochondria-mediated apoptotic GCs phagocytosis in SCs.
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影响因子：
64.5
作者：
Wang Y;Subramanian M;Yurdagul A Jr;Barbosa-Lorenzi VC;Cai B;de Juan-Sanz J;Ryan TA;Nomura M;Maxfield FR;Tabas I
通讯作者：
Tabas I
影响因子：
3.6
作者：
Bhattacharjee, Rahul;Goswami, Suranjana;Vijayaraghavan, Srinivasan
通讯作者：
Vijayaraghavan, Srinivasan
影响因子：
16.6
作者：
Panneerdoss S;Viswanadhapalli S;Abdelfattah N;Onyeagucha BC;Timilsina S;Mohammad TA;Chen Y;Drake M;Vuori K;Kumar TR;Rao MK
通讯作者：
Rao MK
影响因子：
64.8
作者：
Park, Daeho;Han, Claudia Z.;Elliott, Michael R.;Kinchen, Jason M.;Trampont, Paul C.;Das, Soumita;Collins, Sheila;Lysiak, Jeffrey J.;Hoehn, Kyle L.;Ravichandran, Kodi S.
通讯作者：
Ravichandran, Kodi S.
影响因子：
5.2
作者：
Chang CR;Blackstone C
通讯作者：
Blackstone C