Neuraminidase of Influenza A Virus Binds Lysosome-Associated Membrane Proteins Directly and Induces Lysosome Rupture.

Abstract

UNLABELLED:

As a recycling center, lysosomes are filled with numerous acid hydrolase enzymes that break down waste materials and invading pathogens. Recently, lysosomal cell death has been defined as "lysosomal membrane permeabilization and the consequent leakage of lysosome contents into cytosol." Here, we show that the neuraminidase (NA) of H5N1 influenza A virus markedly deglycosylates and degrades lysosome-associated membrane proteins (LAMPs; the most abundant membrane proteins of lysosome), which induces lysosomal rupture, and finally leads to cell death of alveolar epithelial carcinoma A549 cells and human tracheal epithelial cells. The NA inhibitors peramivir and zanamivir could effectively block the deglycosylation of LAMPs, inhibit the virus cell entry, and prevent cell death induced by the H5N1 influenza virus. The NA of seasonal H1N1 virus, however, does not share these characteristics. Our findings not only reveal a novel role of NA in the early stage of the H5N1 influenza virus life cycle but also elucidate the molecular mechanism of lysosomal rupture crucial for influenza virus induced cell death.

IMPORTANCE:

The integrity of lysosomes is vital for maintaining cell homeostasis, cellular defense and clearance of invading pathogens. This study shows that the H5N1 influenza virus could induce lysosomal rupture through deglycosylating lysosome-associated membrane proteins (LAMPs) mediated by the neuraminidase activity of NA protein. NA inhibitors such as peramivir and zanamivir could inhibit the deglycosylation of LAMPs and protect lysosomes, which also further interferes with the H5N1 influenza virus infection at early stage of life cycle. This work is significant because it presents new concepts for NA's function, as well as for influenza inhibitors' mechanism of action, and could partially explain the high mortality and high viral load after H5N1 virus infection in human beings and why NA inhibitors have more potent therapeutic effects for lethal avian influenza virus infections at early stage.

• Authors: Xiangwu Ju, Yiwu Yan, Qiang Liu, Ning Li, Miaomiao Sheng, Lifang Zhang, Xiao Li, Zhu Liang, Fengming Huang, Kangtai Liu, Yan Zhao, Yanxu Zhang, Zhen Zou, Jianchao Du, Ying Zhong, Huandi Zhou, Peng Yang, Huijun Lu, Mingyao Tian, Dangsheng Li, Jianming Zhang, Ningyi Jin, Chengyu Jiang
• Journal: Journal of virology (J Virol) Vol. 89 Issue 20 Pg. 10347-58 (Oct 2015) ISSN: 1098-5514 [Electronic] United States
• PMID: 26246576 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Chemical References

• Acids, Carbocyclic
• Cyclopentanes
• Enzyme Inhibitors
• Guanidines
• Lysosome-Associated Membrane Glycoproteins
• Viral Proteins
• Neuraminidase
• Zanamivir
• peramivir

Topics

• Acids, Carbocyclic
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Membrane (chemistry, enzymology)
• Cyclopentanes (pharmacology)
• Cytosol (drug effects, enzymology, virology)
• Enzyme Inhibitors (pharmacology)
• Epithelial Cells (drug effects, virology)
• Guanidines (pharmacology)
• Humans
• Hydrolysis
• Influenza A Virus, H1N1 Subtype (chemistry, enzymology)
• Influenza A Virus, H5N1 Subtype (chemistry, enzymology)
• Lysosome-Associated Membrane Glycoproteins (chemistry, metabolism)
• Lysosomes (drug effects, enzymology, virology)
• Neuraminidase (metabolism)
• Protein Binding
• Proteolysis
• Respiratory Mucosa (drug effects, virology)
• Species Specificity
• Viral Proteins (metabolism)
• Virus Internalization (drug effects)
• Zanamivir (pharmacology)