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Journal of Zhejiang University SCIENCE B
ISSN 1673-1581(Print), 1862-1783(Online), Monthly
2024 Vol.25 No.6 P.485-498
Sialyltransferase ST3GAL6 silencing reduces α2,3-sialylated glycans to regulate autophagy by decreasing HSPB8-BAG3 in the brain with hepatic encephalopathy
Abstract: End-stage liver diseases, such as cirrhosis and liver cancer caused by hepatitis B, are often combined with hepatic encephalopathy (HE); ammonia poisoning is posited as one of its main pathogenesis mechanisms. Ammonia is closely related to autophagy, but the molecular mechanism of ammonia’s regulatory effect on autophagy in HE remains unclear. Sialylation is an essential form of glycosylation. In the nervous system, abnormal sialylation affects various physiological processes, such as neural development and synapse formation. ST3 β-galactoside α2,3-sialyltransferase 6 (ST3GAL6) is one of the significant glycosyltransferases responsible for adding α2,3-linked sialic acid to substrates and generating glycan structures. We found that the expression of ST3GAL6 was upregulated in the brains of mice with HE and in astrocytes after ammonia induction, and the expression levels of α2,3-sialylated glycans and autophagy-related proteins microtubule-associated protein light chain 3 (LC3) and Beclin-1 were upregulated in ammonia-induced astrocytes. These findings suggest that ST3GAL6 is related to autophagy in HE. Therefore, we aimed to determine the regulatory relationship between ST3GAL6 and autophagy. We found that silencing ST3GAL6 and blocking or degrading α2,3-sialylated glycans by way of Maackia amurensis lectin-II (MAL-II) and neuraminidase can inhibit autophagy. In addition, silencing the expression of ST3GAL6 can downregulate the expression of heat shock protein β8 (HSPB8) and Bcl2-associated athanogene 3 (BAG3). Notably, the overexpression of HSPB8 partially restored the reduced autophagy levels caused by silencing ST3GAL6 expression. Our results indicate that ST3GAL6 regulates autophagy through the HSPB8-BAG3 complex.
Key words: Hepatic encephalopathy; Hyperammonemia; Autophagy; ST3 β-galactoside α2,3-sialyltransferase 6 (ST3GAL6); Heat shock protein β8 (HSPB8)
1西北大学生命科学学院功能糖组学实验室，中国西安市，710069
2第四军医大学细胞生物学教研室&国家分子医学转化中心，中国西安市，710032
3陕西中医药大学医学实验中心，中国咸阳市，712046
4上海市浦东新区公利医院传染病科，中国上海市，200135
摘要：肝性脑病（HE）是肝病（如乙型肝炎引起的肝硬化和肝癌）发展到终末期之后的一个常见的并发症，氨中毒被认为是其主要的发病机制之一。氨与自噬密切相关，但其对HE的自噬调节作用的分子机制尚不清楚。唾液酸化是糖基化的一种重要形式。在神经系统中，异常的唾液酸化会影响各种生理过程，例如神经发育和突触形成。ST3 β-半乳糖苷α2,3-唾液酸转移酶6（ST3GAL6）是一种重要的糖基转移酶，负责将α2,3-连接的唾液酸添加到底物并生成聚糖结构。在本研究中，我们发现经氨诱导后，HE小鼠大脑和星形胶质细胞中ST3GAL6的表达上调，并且在氨诱导的星形胶质细胞中，α2,3-唾液酸化聚糖和自噬相关蛋白微管相关蛋白轻链3（LC3）和Beclin-1的表达均上调。上述结果表明：ST3GAL6与HE中的自噬有关。因此，本研究将进一步确定ST3GAL6与自噬之间的调控关系。我们发现通过沉默ST3GAL6以及通过怀槐凝集素-II（MAL-II）和神经氨酸酶阻断或降解α2,3-唾液酸化聚糖可以抑制自噬。此外，沉默ST3GAL6的表达可以下调热休克蛋白β8（HSPB8）和Bcl2关联永生基因3（BAG3）的表达。值得注意的是，HSPB8的过表达可部分恢复因ST3GAL6表达沉默而导致的自噬水平降低。综上，我们的结果表明了ST3GAL6可通过HSPB8-BAG3复合物调节自噬。
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DOI:
10.1631/jzus.B2300917
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On-line Access:
2024-06-24
Received:
2023-12-17
Revision Accepted:
2024-02-20
Crosschecked:
2024-06-24