Site-specific glycosylation regulates the form and function of the intermediate filament cytoskeleton.
Site-specific glycosylation regulates the form and function of the intermediate filament cytoskeleton.
复制标题
DOI：
10.7554/elife.31807
复制
发表时间：
2018-03-07
期刊：
影响因子：
7.7
通讯作者：
Boyce M
中科院分区：
文献类型：
--
作者：
Tarbet HJ;Dolat L;Smith TJ;Condon BM;O'Brien ET 3rd;Valdivia RH;Boyce M
Intermediate filaments (IF) are a major component of the metazoan cytoskeleton and are essential for normal cell morphology, motility, and signal transduction. Dysregulation of IFs causes a wide range of human diseases, including skin disorders, cardiomyopathies, lipodystrophy, and neuropathy. Despite this pathophysiological significance, how cells regulate IF structure, dynamics, and function remains poorly understood. Here, we show that site-specific modification of the prototypical IF protein vimentin with O-linked β-N-acetylglucosamine (O-GlcNAc) mediates its homotypic protein-protein interactions and is required in human cells for IF morphology and cell migration. In addition, we show that the intracellular pathogen Chlamydia trachomatis, which remodels the host IF cytoskeleton during infection, requires specific vimentin glycosylation sites and O-GlcNAc transferase activity to maintain its replicative niche. Our results provide new insight into the biochemical and cell biological functions of vimentin O-GlcNAcylation, and may have broad implications for our understanding of the regulation of IF proteins in general. Like the body's skeleton, the cytoskeleton gives shape and structure to the inside of a cell. Yet, unlike a skeleton, the cytoskeleton is ever changing. The cytoskeleton consists of many fibers each made from chains of protein molecules. One of these proteins is called vimentin and it forms intermediate filaments in the cytoskeleton. Many different types of cells contain vimentin and a lot of it is found in cancer cells that have spread beyond their original location to other sites in the body. Cells use chemical modifications to regulate cytoskeleton proteins. For example, through a process called glycosylation, cells can reversibly attach a sugar modification called O-GlcNAc to vimentin. O-GlcNAc can be attached to several different parts of vimentin and each location may have a different effect. It is not currently clear how cells control their vimentin filaments or what role O-GlcNAc plays in this process. Using genetic engineering, Tarbet et al. produced human cells in the laboratory with modified vimentin proteins. These altered proteins lacked some of the sites for O-GlcNAc attachment. The goal was to see whether the loss of O-GlcNAc at a specific location would affect fiber formation and cell behavior. The results showed one site where vimentin needs O-GlcNAc to form fibers. Without O-GlcNAc at this site, cells could not migrate towards chemical signals. In addition, in normal human cells, Chlamydia bacteria hijack vimentin and rearrange the filaments to form a cage around themselves for protection. However, the cells lacking O-GlcNAc on vimentin were resistant to infection by Chlamydia bacteria. These findings highlight the importance of O-GlcNAc on vimentin in healthy cells and during infection. Vimentin’s contribution to cell migration may also help to explain its role in the spread of cancer. The importance of O-GlcNAc suggests it could be a new target for therapies. Yet, it also highlights the need for caution due to the delicate balance between the activity of vimentin in healthy and diseased cells. In addition, human cells produce about 70 other vimentin-like proteins and further work will examine if they are also affected by O-GlcNAc.
