Jamaludin Mohamad Ikhwan, Wakabayashi Sadao, Taniguchi Mai, Sasaki Kanae, Komori Ryota, Kawamura Hirotada, Takase Hayataka, Sakamoto Miyu, Yoshida Hiderou
Department of Molecular Biochemistry, Graduate School of Life Science, University of Hyogo.
Cell Struct Funct. 2019 Oct 31;44(2):137-151. doi: 10.1247/csf.19009. Epub 2019 Oct 19.
The Golgi apparatus is an organelle where membrane or secretory proteins receive post-translational modifications such as glycosylation and sulfation, after which the proteins are selectively transported to their final destinations through vesicular transport. When the synthesis of secretory or membrane proteins is increased and overwhelms the capacity of the Golgi (Golgi stress), eukaryotic cells activate a homeostatic mechanism called the Golgi stress response to augment the capacity of the Golgi. Four response pathways of the Golgi stress response have been identified, namely the TFE3, CREB3, HSP47, and proteoglycan pathways, which regulate the general function of the Golgi, apoptosis, cell survival, and proteoglycan glycosylation, respectively. Here, we identified a novel response pathway that augments the expression of glycosylation enzymes for mucins in response to insufficiency in mucin-type glycosylation in the Golgi (mucin-type Golgi stress), and we found that expression of glycosylation enzymes for mucins such as GALNT5, GALNT8, and GALNT18 was increased upon mucin-type-Golgi stress. We named this pathway the mucin pathway. Unexpectedly, mucin-type Golgi stress induced the expression and activation of TFE3, a key transcription factor regulating the TFE3 pathway, suggesting that the activated mucin pathway sends a crosstalk signal to the TFE3 pathway. We identified an enhancer element regulating transcriptional induction of TFE3 upon mucin-type Golgi stress, and named it the mucin-type Golgi stress response element, of which consensus was ACTTCC(N9)TCCCCA. These results suggested that crosstalk from the mucin pathway to the TFE3 pathway has an important role in the regulation of the mammalian Golgi stress response.Key words: Golgi stress, mucin, TFE3, organelle autoregulation, organelle zone.
高尔基体是一种细胞器，膜蛋白或分泌蛋白在此接受翻译后修饰，如糖基化和硫酸化，之后这些蛋白质通过囊泡运输被选择性地转运到它们的最终目的地。当分泌蛋白或膜蛋白的合成增加并超过高尔基体的容量（高尔基体应激）时，真核细胞会激活一种称为高尔基体应激反应的稳态机制来增强高尔基体的容量。已确定高尔基体应激反应的四条反应途径，即TFE3、CREB3、HSP47和蛋白聚糖途径，它们分别调节高尔基体的一般功能、细胞凋亡、细胞存活和蛋白聚糖糖基化。在此，我们鉴定出一条新的反应途径，该途径可响应高尔基体中粘蛋白型糖基化不足（粘蛋白型高尔基体应激）而增强粘蛋白糖基化酶的表达，并且我们发现，在粘蛋白型高尔基体应激时，诸如GALNT5、GALNT8和GALNT18等粘蛋白糖基化酶的表达会增加。我们将此途径命名为粘蛋白途径。出乎意料的是，粘蛋白型高尔基体应激诱导了TFE3（一种调节TFE3途径的关键转录因子）的表达和激活，这表明激活的粘蛋白途径向TFE3途径发送了一个串扰信号。我们鉴定出一个调节粘蛋白型高尔基体应激时TFE3转录诱导的增强子元件，并将其命名为粘蛋白型高尔基体应激反应元件，其共有序列为ACTTCC(N9)TCCCCA。这些结果表明，从粘蛋白途径到TFE3途径的串扰在哺乳动物高尔基体应激反应的调节中具有重要作用。关键词：高尔基体应激；粘蛋白；TFE3；细胞器自调节；细胞器区室
