Hyaluronan synthase 1: a mysterious enzyme with unexpected functions.
Hyaluronan synthase 1: a mysterious enzyme with unexpected functions.
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DOI：
10.3389/fimmu.2015.00043
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发表时间：
2015
影响因子：
7.3
通讯作者：
Rilla K
中科院分区：
文献类型：
--
作者：
Siiskonen H;Oikari S;Pasonen-Seppänen S;Rilla K
乙酰透明质酸合酶 1 (HAS1) 是负责细胞乙酰透明质酸合成的三种同工酶之一。人们对 HAS1 的兴趣有限，因为与具有较高酶活性的其他两种同工酶 HAS2 和 HAS3 相比，它在透明质酸生产中的作用似乎微不足道。此外，在迄今为止研究的大多数细胞类型中，其基因表达量较低，并且即使在细胞培养物中过度表达，该酶也需要高浓度的糖前体来合成透明质酸。 HAS1 的表达和活性均由白细胞介素和细胞因子等促炎因子诱导，表明其与炎症状况有关。 Has1 在与炎症相关的状态下表达上调，例如动脉粥样硬化、骨关节炎和传染性肺病。此外，HAS1 的全长变体和剪接变体均在膀胱癌、前列腺癌、多发性骨髓瘤和恶性间皮瘤等恶性肿瘤中表达。有趣的是，组织切片的免疫染色证明了 HAS1 作为乳腺癌的不良预测因子的作用，并且与高复发率和短总生存期相关。利用荧光标记蛋白揭示了 HAS1 的细胞内分布模式，与其他同工酶不同。在迄今为止研究的所有细胞类型中，高比例的 HAS1 积累在细胞内，在质膜及其突起上检测到微弱的信号。此外，HAS1 产生的细胞周透明质酸外壳通常很薄，无需炎症因子或血糖应激诱导，并且取决于 CD44-HA 相互作用。这些特定的相互作用在炎症反应期间调节透明质酸组织成白细胞募集基质。尽管 HAS1 在正常情况下的酶活性明显较小，但在代谢综合征、炎症和癌症等与血糖应激相关的情况下，它可能是一个重要因素。
Hyaluronan synthase 1 (HAS1) is one of three isoenzymes responsible for cellular hyaluronan synthesis. Interest in HAS1 has been limited because its role in hyaluronan production seems to be insignificant compared to the two other isoenzymes, HAS2 and HAS3, which have higher enzymatic activity. Furthermore, in most cell types studied so far, the expression of its gene is low and the enzyme requires high concentrations of sugar precursors for hyaluronan synthesis, even when overexpressed in cell cultures. Both expression and activity of HAS1 are induced by pro-inflammatory factors like interleukins and cytokines, suggesting its involvement in inflammatory conditions. Has1 is upregulated in states associated with inflammation, like atherosclerosis, osteoarthritis, and infectious lung disease. In addition, both full length and splice variants of HAS1 are expressed in malignancies like bladder and prostate cancers, multiple myeloma, and malignant mesothelioma. Interestingly, immunostainings of tissue sections have demonstrated the role of HAS1 as a poor predictor in breast cancer, and is correlated with high relapse rate and short overall survival. Utilization of fluorescently tagged proteins has revealed the intracellular distribution pattern of HAS1, distinct from other isoenzymes. In all cell types studied so far, a high proportion of HAS1 is accumulated intracellularly, with a faint signal detected on the plasma membrane and its protrusions. Furthermore, the pericellular hyaluronan coat produced by HAS1 is usually thin without induction by inflammatory agents or glycemic stress and depends on CD44–HA interactions. These specific interactions regulate the organization of hyaluronan into a leukocyte recruiting matrix during inflammatory responses. Despite the apparently minor enzymatic activity of HAS1 under normal conditions, it may be an important factor under conditions associated with glycemic stress like metabolic syndrome, inflammation, and cancer.
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