<br>MiT/TFE 家族成员抑制 L-亮氨酰-L-亮氨酸甲酯诱导的细胞死亡。,The Journal of Toxicological Sciences

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MiT/TFE 家族成员抑制 L-亮氨酰-L-亮氨酸甲酯诱导的细胞死亡。
The Journal of Toxicological Sciences ( IF 1.8 ) Pub Date : 2021-01-01 , DOI: 10.2131/jts.46.143
Ayaka Yabuki ₁ , Masatsugu Miyara _{1,

2,

3} , Kanae Umeda-Miyara ₁ , Saya Takao ₁ , Seigo Sanoh ₁ , Yaichiro Kotake ₁

Affiliation

溶酶体是细胞稳态所必需的降解细胞器。然而，各种内部和外部刺激，包括L-亮氨酰-L-亮氨酸甲酯（LLOMe）（一种常见的溶酶体药物），会透化溶酶体膜，导致溶酶体依赖性细胞死亡，因为溶酶体内容物渗漏到细胞中。细胞质。小眼/转录因子 E (MiT/TFE) 家族成员，包括转录因子 EB (TFEB)、转录因子 E3 (TFE3) 和小眼相关转录因子 (MITF)，是溶酶体生物发生的主要调节因子，已知参与溶酶体应激反应。然而，它们对与溶酶体膜损伤相关的细胞死亡的保护作用仍然知之甚少。在这项研究中，我们证实LLOMe诱导的溶酶体损伤触发了TFEB/TFE3/MITF的核转位，并增加了HeLa细胞中编码溶酶体水解酶和溶酶体膜蛋白的靶基因的mRNA水平。此外，我们发现 TFEB/TFE3/MITF 敲低加剧了 LLOMe 诱导的细胞死亡。然而，尽管 LLOMe 诱导的 CTSD mRNA 水平增加，但 TFEB 过表达仅略微减弱了 LLOMe 诱导的细胞死亡，这意味着 MiT/TFE 家族成员的内源水平可能足以促进溶酶体生物发生以响应溶酶体膜损伤。我们的结果表明 MiT/TFE 家族成员抑制与溶酶体膜损伤相关的细胞死亡。

"点击查看英文标题和摘要"

MiT/TFE family members suppress L-leucyl-L-leucine methyl ester-induced cell death.

Lysosomes are degradative organelles essential for cell homeostasis. However, various internal and external stimuli, including L-leucyl-L-leucine methyl ester (LLOMe), which is one of the common lysosomotropic agents, permeabilize the lysosomal membrane, leading to lysosome-dependent cell death because of leakage of lysosomal contents to the cytosol. The microphthalmia/transcription factor E (MiT/TFE) family members, which include transcription factor EB (TFEB), transcription factor E3 (TFE3), and microphthalmia-associated transcription factor (MITF), are master regulators of lysosomal biogenesis and are known to be involved in the lysosomal stress response. However, their protective effects against cell death associated with lysosomal-membrane damage are still poorly understood. In this study, we confirmed that LLOMe-induced lysosomal damage triggered nuclear translocation of TFEB/TFE3/MITF and increased the mRNA levels of their target genes encoding lysosomal hydrolases and lysosomal membrane proteins in HeLa cells. Furthermore, we revealed that TFEB/TFE3/MITF knockdown exacerbated LLOMe-induced cell death. However, TFEB overexpression only slightly attenuated LLOMe-induced cell death, despite enhanced LLOMe-induced increase in CTSD mRNA levels, implying that the endogenous levels of MiT/TFE family members might be sufficient to promote lysosomal biogenesis in response to lysosomal-membrane damage. Our results suggest that MiT/TFE family members suppress the cell death associated with lysosomal-membrane damage.

更新日期：2021-01-01

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