Differential phosphorylation determines the repressor and activator potencies of GLI1 proteins and their efficiency in modulating the HPV life cycle
Differential phosphorylation determines the repressor and activator potencies of GLI1 proteins and their efficiency in modulating the HPV life cycle
复制标题
DOI：
10.1371/journal.pone.0225775
复制
发表时间：
2019-11-26
期刊：
影响因子：
3.7
通讯作者：
Piirsoo, Marko
中科院分区：
文献类型：
--
作者：
Piirsoo, Alla;Pink, Anne;Piirsoo, Marko
Sonic Hedgehog（Shh）信号通路在胚胎发育和病理条件下起着多种作用。虽然Shh通路的核心组分是保守的，但信号转导的调节在物种和细胞类型之间显著不同。蛋白激酶Ulk 3和Pka作为Gli转录因子活性的调节剂参与Shh途径，Gli转录因子是信号的核介质。在这里，我们研究了两种GLI 1亚型，全长GLI 1（GLI 1FL）和GLI 1 Delta N的调节和活动。后一种蛋白缺乏前128个氨基酸，包括保守的磷酸化簇和SUFU的结合基序，SUFU是GLI活性的关键调节因子。两种GLI 1亚型在分析的所有人细胞系中共表达，并具有相似的DNA结合活性。ULK 3增强两种GLI 1蛋白的转录活性，而PKA抑制GLI 1 Delta N的活性，但不抑制GLI 1FL。除了其作为转录激活因子的作用外，GLI 1FL还通过抑制人乳头瘤病毒18型（HPV 18）早期启动子的转录来作为阻遏物。此外，与GLI 1 Delta N相比，GLI 1FL是几种HPV类型复制的更有效抑制剂。总之，我们的数据表明，GLI 1FL的N-末端部分是至关重要的实现其作为一个转录调节剂的全部潜力。
The Sonic Hedgehog (Shh) signalling pathway plays multiple roles during embryonic development and under pathological conditions. Although the core components of the Shh pathway are conserved, the regulation of signal transduction varies significantly among species and cell types. Protein kinases Ulk3 and Pka are involved in the Shh pathway as modulators of the activities of Gli transcription factors, which are the nuclear mediators of the signal. Here, we investigate the regulation and activities of two GLI1 isoforms, full-length GLI1 (GLI1FL) and GLI1 Delta N. The latter protein lacks the first 128 amino acids including the conserved phosphorylation cluster and the binding motif for SUFU, the key regulator of GLI activity. Both GLI1 isoforms are co-expressed in all human cell lines analysed and possess similar DNA binding activity. ULK3 potentiates the transcriptional activity of both GLI1 proteins, whereas PKA inhibits the activity of GLI1 Delta N, but not GLI1FL. In addition to its wellestablished role as a transcriptional activator, GLI1FL acts as a repressor by inhibiting transcription from the early promoters of human papillomavirus type 18 (HPV18). Additionally, compared to GLI1 Delta N, GLI1FL is a more potent suppressor of replication of several HPV types. Altogether, our data show that the N-terminal part of GLI1FL is crucial for the realization of its full potential as a transcriptional regulator.