Polyamines stimulate the CHSY1 synthesis through the unfolding of the RNA G-quadruplex at the 5′-untraslated region
Polyamines stimulate the CHSY1 synthesis through the unfolding of the RNA G-quadruplex at the 5′-untraslated region
复制标题
DOI：
10.1042/bcj20180672
复制
发表时间：
2018-12-12
影响因子：
4.1
通讯作者：
Higashi, Kyohei
中科院分区：
文献类型：
--
作者：
Yamaguchi, Katsutoshi;Asakura, Kiryu;Higashi, Kyohei
糖胺聚糖（Glycosaminoglycans, GAGs）是一类结构相关的酸性多糖，主要存在于蛋白聚糖（proteoglycans, pg）的聚糖部分。其中硫酸软骨素（chondroitin sulfate， CS）和硫酸皮肤素（dermatan sulfate）作为pg的侧链，广泛分布于动物体内，并表现出不同的结构变化，如硫酸化模式和外聚化程度，通过与生长因子、chennokines和粘附分子的相互作用来实现其生理功能。然而，CS的结构变化，特别是4-0-硫酸化与6-0-硫酸化的比例（4S/6S）和CS链长在老化过程中发生的变化尚未完全了解。我们发现，在多胺缺失的细胞中，CS的4S/6S比和分子量降低。此外，多胺消耗还观察到软骨素合成酶1 （CHSY1）和软骨素4- o -硫转移酶2蛋白水平下降。有趣的是，CHSY1的翻译起始被一个高度结构化的序列（相对于起始密码子的位置202至117）抑制，该序列在5'-非翻译区含有RNA g -四重体（G4）结构。G4s的形成受到G4s邻近序列的影响，当G4s的形成被定点诱变抑制时，多胺对CHSY1合成的刺激消失。这些结果表明，多胺对G4结构的破坏刺激了CHSY1的合成，至少在一定程度上促进了CS链的成熟。
Glycosaminoglycans (GAGs), a group of structurally related acidic polysaccharides, are primarily found as glycan moieties of proteoglycans (PGs). Among these, chondroitin sulfate (CS) and dermatan sulfate, side chains of PGs, are widely distributed in animal kingdom and show structural variations, such as sulfation patterns and degree of epimerization, which are responsible for their physiological functions through interactions with growth factors, chennokines and adhesion molecules. However, structural changes in CS, particularly the ratio of 4-0-sulfation to 6-0-sulfation (4S/6S) and CS chain length that occur during the aging process, are not fully understood. We found that 4S/6S ratio and molecular weight of CS were decreased in polyamine-depleted cells. In addition, decreased levels of chondroitin synthase 1 (CHSY1) and chondroitin 4-O-sulfotransferase 2 proteins were also observed on polyamine depletion. Interestingly, the translation initiation of CHSY1 was suppressed by a highly structured sequence (positions 202 to 117 relative to the initiation codon) containing RNA G-quadruplex (G4) structures in 5'-untranslated region. The formation of the G4s was influenced by the neighboring sequences to the G4s and polyamine stimulation of CHSY1 synthesis disappeared when the formation of the G4s was inhibited by site-directed mutagenesis. These results suggest that the destabilization of G4 structures by polyamines stimulates CHSY1 synthesis and, at least in part, contribute to the maturation of CS chains.