Sialyltransferase ST3GAL6 silencing reduces α2,3-sialylated glycans to regulate autophagy by decreasing HSPB8-BAG3 in the brain with hepatic encephalopathy

Xiaocheng LI; Yaqing XIAO; Pengfei LI; Yayun ZHU; Yonghong GUO; Huijie BIAN; Zheng LI

doi:10.1631/jzus.B2300917

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Sialyltransferase ST3GAL6 silencing reduces α2,3-sialylated glycans to regulate autophagy by decreasing HSPB8-BAG3 in the brain with hepatic encephalopathy

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Research Article | Updated：2024-06-24

Sialyltransferase ST3GAL6 silencing reduces α2,3-sialylated glycans to regulate autophagy by decreasing HSPB8-BAG3 in the brain with hepatic encephalopathy
Sialyltransferase ST3GAL6 silencing reduces α2,3-sialylated glycans to regulate autophagy by decreasing HSPB8-BAG3 in the brain with hepatic encephalopathy
唾液酸糖基转移酶ST3GAL6的沉默可通过减少α2,3-唾液酸化聚糖降低HSPB8-BAG3表达从而调控肝性脑病小鼠大脑中的自噬
Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) Vol. 25, Issue 6, Pages: 485-498(2024)
Affiliations：

1.Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi’an 710069, China
2.National Translational Science Center for Molecular Medicine, Department of Cell Biology, Fourth Military Medical University, Xi’an 710032, China
3.Medical Experiment Center, Shaanxi University of Chinese Medicine, Xianyang 712046, China
4.The Infectious Disease Department, Gongli Hospital, Pudong New Area, Shanghai 200135, China
Funds：
DOI：10.1631/jzus.B2300917
CLC：
CSTR：
Published： 15 June 2024 ，

Published Online： 15 May 2024 ，

Received： 17 December 2023 ，

Revised： 20 February 2024 ，

李小承,肖雅清,李鹏飞等.唾液酸糖基转移酶ST3GAL6的沉默可通过减少α2,3-唾液酸化聚糖降低HSPB8-BAG3表达从而调控肝性脑病小鼠大脑中的自噬[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2024,25(06):485-498.

Xiaocheng LI, Yaqing XIAO, Pengfei LI, et al. Sialyltransferase ST3GAL6 silencing reduces α2,3-sialylated glycans to regulate autophagy by decreasing HSPB8-BAG3 in the brain with hepatic encephalopathy. [J]. Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) 25(6):485-498(2024)
李小承,肖雅清,李鹏飞等.唾液酸糖基转移酶ST3GAL6的沉默可通过减少α2,3-唾液酸化聚糖降低HSPB8-BAG3表达从而调控肝性脑病小鼠大脑中的自噬[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2024,25(06):485-498. DOI： 10.1631/jzus.B2300917.

Xiaocheng LI, Yaqing XIAO, Pengfei LI, et al. Sialyltransferase ST3GAL6 silencing reduces α2,3-sialylated glycans to regulate autophagy by decreasing HSPB8-BAG3 in the brain with hepatic encephalopathy. [J]. Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) 25(6):485-498(2024) DOI： 10.1631/jzus.B2300917.

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。

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.

关键词

肝性脑病高氨血症自噬ST3 β-半乳糖苷α23-唾液酸转移酶6（ST3GAL6）热休克蛋白β8（HSPB8）

Keywords

Hepatic encephalopathyHyperammonemiaAutophagyST3 β-galactoside α23-sialyltransferase 6 (ST3GAL6)Heat shock protein β8 (HSPB8)

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