Basal Autophagy Deficiency Causes Thyroid Follicular Epithelial Cell Death in Mice
Basal Autophagy Deficiency Causes Thyroid Follicular Epithelial Cell Death in Mice
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DOI：
10.1210/en.2019-00312
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发表时间：
2019-09-01
期刊：
影响因子：
4.8
通讯作者：
Nagayama, Yuji
中科院分区：
文献类型：
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作者：
Kurashige, Tomomi;Nakajima, Yasuyo;Nagayama, Yuji
自噬是一种分解代谢过程，涉及通过溶酶体机制降解细胞组分，将营养物质从不必要的过程重新定位到生存所需的更关键的过程。据报道，Atg 5或Atg 7基因（自噬的一个组成部分）的系统性破坏是致命的，并且其组织特异性破坏导致几个器官中的组织变性。然而，甲状腺自噬的功能意义仍然未知。我们的初步数据表明，功能失调的自噬可能参与辐射诱导的甲状腺癌的发生。因此，我们评估Atg 5基因敲除（KO）对甲状腺形态和功能的影响。为此，将Atg 5（Thyrilflox）小鼠与TPO-Cre小鼠杂交，产生甲状腺滤泡上皮细胞（甲状腺细胞）特异性ATG 5缺陷小鼠（Atg 5（thyr-KO/）（KO））。通过缺乏ATG 5表达证实了ATG 5基因KO，并且通过微管相关蛋白1轻链3-II斑点的减少和p62的增加证明了自噬的破坏。Atg 5（thyr-KO/）（KO）小鼠出生正常，甲状腺形态、甲状腺重量以及血清T4和TSH水平在4个月时几乎正常。然而，在8个月和12个月时，在Atg 5（thyr-KO/）（KO）小鼠中观察到甲状腺细胞数量减少和TUNEL+-甲状腺细胞增加，尽管甲状腺功能仍然正常。不规则形状（椭圆形）的卵泡数量也增加。Atg 5（thyr-KO/）（KO）小鼠中8-羟基-2 '-脱氧鸟苷和53 BP 1病灶增加表明过度氧化应激。这些数据表明，甲状腺细胞在缺乏基础水平的自噬的情况下逐渐经历降解/细胞死亡，表明自噬对于甲状腺细胞的质量控制至关重要。
Autophagy is a catabolic process that involves the degradation of cellular components through the lysosomal machinery, relocating nutrients from unnecessary processes to more pivotal processes required for survival. It has been reported that systemic disruption of the Atg5 or Atg7 gene, a component of autophagy, is lethal and that its tissue-specific disruption causes tissue degeneration in several organs. However, the functional significance of autophagy in the thyroid glands remains unknown. Our preliminary data imply the possible involvement of dysfunctional autophagy in radiation-induced thyroid carcinogenesis. Therefore, we evaluated the effect of Atg5 gene knockout (KO) on thyroid morphology and function. To this end, Atg5(floxlflox) mice were crossed with TPO-Cre mice, yielding the thyroid follicular epithelial cell (thyrocyte)-specific ATG5-deficient mice (Atg5(thyr-KO/)(KO)). Atg5 gene KO was confirmed by a lack of ATG5 expression, and disruption of autophagy was demonstrated by a decrease in microtubule-associated protein 1 light chain 3-II puncta and an increase in p62. Atg5(thyr-KO/)(KO) mice were born normally, and thyroid morphology, thyroid weights, and serum T4 and TSH levels were almost normal at 4 months. However, at 8 and 12 months, a decrease in the number of thyrocytes and an increase in TUNEL+-thyrocytes were observed in Atg5(thyr-KO/)(KO) mice even though thyroid function was still normal. The number of irregularly shaped (gourd-shaped) follicles was also increased. Excess oxidative stress was indicated by increased 8-hydroxy-2'-deoxyguanosine and 53BP1 foci in Atg5(thyr-KO/)(KO) mice. These data demonstrate that thyrocytes gradually undergo degradation/cell death in the absence of basal levels of autophagy, indicating that autophagy is critical for the quality control of thyrocytes.