Functional Implications of O-GlcNAcylation-dependent Phosphorylation at a Proximal Site on Keratin 18

Kakade, Poonam; Budnar, Srikanth; Kalraiya, Rajiv D.; Vaidya, Milind M.

doi:10.1074/jbc.m116.728717

Cited by 20 publications

(18 citation statements)

References 59 publications

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“…In addition, site-specific O-GlcNAcylation of vimentin is exploited by an intracellular pathogen to promote its own replication, underlining the importance of IF dynamics in disease states. Because many IF proteins are O-GlcNAc-modified ( King and Hounsell, 1989 ; Chou et al, 1992 ; Ku et al, 2010 ; Dong et al, 1996 ; Dong et al, 1993 ; Lüdemann et al, 2005 ; Deng et al, 2008 ; Cheung and Hart, 2008 ; Slawson et al, 2008 ; Wang et al, 2007 ; Srikanth et al, 2010 ; Kakade et al, 2016 ; Tao et al, 2006 ), our results may provide new insight into the regulation of both vimentin in particular and the IF cytoskeleton in general.…”

Section: Discussionmentioning

confidence: 73%

“…In addition, our work may have broad implications for other IF proteins. Numerous IF proteins are dynamically glycosylated in vivo ( King and Hounsell, 1989 ; Chou et al, 1992 ; Ku et al, 2010 ; Dong et al, 1996 ; Dong et al, 1993 ; Lüdemann et al, 2005 ; Deng et al, 2008 ; Cheung and Hart, 2008 ; Slawson et al, 2008 ; Wang et al, 2007 ; Srikanth et al, 2010 ; Kakade et al, 2016 ; Tao et al, 2006 ), and the S49 residue of vimentin is conserved both among vertebrate vimentin orthologs and in human desmin, another type III IF protein ( Figure 6—figure supplement 1 ). Therefore, site-specific O-GlcNAcylation may be a general mode of regulating IF dynamics and function.…”

Section: Discussionmentioning

confidence: 99%

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Site-specific glycosylation regulates the form and function of the intermediate filament cytoskeleton

Tarbet

Dolat

Smith

et al. 2018

eLife

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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.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Site-specific glycosylation regulates the form and function of the intermediate filament cytoskeleton

Tarbet

Dolat

Smith

et al. 2018

eLife

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“…Subsequent use of kinase inhibitors and/or site-directed mutagenesis of key vimentin phosphorylation consensus sites may be successful in addressing their respective roles in Hic-5-dependent organization of the vimentin network. However, to the best of our knowledge, there is no single phospho site mutation of vimentin known to cause network collapse, while mutation of one or more phospho sites in keratin IFs has been shown to promote their collapse, suggesting a complex interrelationship (Kakade et al, 2016;Sawant et al, 2018).…”

Section: Discussionmentioning

confidence: 96%

The focal adhesion scaffold protein Hic-5 regulates vimentin organization in fibroblasts

Vohnoutka

Gulvady

Goreczny

et al. 2019

MBoC

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Focal adhesion (FA)-stimulated reorganization of the F-actin cytoskeleton regulates cellular size, shape, and mechanical properties. However, FA cross-talk with the intermediate filament cytoskeleton is poorly understood. Genetic ablation of the FA-associated scaffold protein Hic-5 in mouse cancer-associated fibroblasts (CAFs) promoted a dramatic collapse of the vimentin network, which was rescued following EGFP-Hic-5 expression. Vimentin collapse correlated with a loss of detergent-soluble vimentin filament precursors and decreased vimentin S72/S82 phosphorylation. Additionally, fluorescence recovery after photobleaching analysis indicated impaired vimentin dynamics. Microtubule (MT)-associated EB1 tracking and Western blotting of MT posttranslational modifications indicated no change in MT dynamics that could explain the vimentin collapse. However, pharmacological inhibition of the RhoGTPase Cdc42 in Hic-5 knockout CAFs rescued the vimentin collapse, while pan-formin inhibition with SMIFH2 promoted vimentin collapse in Hic-5 heterozygous CAFs. Our results reveal novel regulation of vimentin organization/dynamics by the FA scaffold protein Hic-5 via modulation of RhoGTPases and downstream formin activity.

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“…Many studies have revealed the ubiquitous role of O -GlcNAcylation in biological processes, such as gene expression [ 3 , 4 ], cell cycle control [ 4 , 5 ], and regulation of enzyme activity [ 6 , 7 , 8 , 9 ]. Moreover, OGT competes with kinases for the modification site, leading to competition and cross-regulation of these translational modifications [ 9 , 10 , 11 ]. Dysfunction in the O-GlcNAcylation pathway has been associated with various chronic diseases [ 9 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Overview of the Assays to Probe O-Linked β-N-Acetylglucosamine Transferase Binding and Activity

2021

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O-GlcNAcylation is a posttranslational modification that occurs at serine and threonine residues of protein substrates by the addition of O-linked β-d-N-acetylglucosamine (GlcNAc) moiety. Two enzymes are involved in this modification: O-GlcNac transferase (OGT), which attaches the GlcNAc residue to the protein substrate, and O-GlcNAcase (OGA), which removes it. This biological balance is important for many biological processes, such as protein expression, cell apoptosis, and regulation of enzyme activity. The extent of this modification has sparked interest in the medical community to explore OGA and OGT as therapeutic targets, particularly in degenerative diseases. While some OGA inhibitors are already in phase 1 clinical trials for the treatment of Alzheimer’s disease, OGT inhibitors still have a long way to go. Due to complex expression and instability, the discovery of potent OGT inhibitors is challenging. Over the years, the field has grappled with this problem, and scientists have developed a number of techniques and assays. In this review, we aim to highlight assays and techniques for OGT inhibitor discovery, evaluate their strength for the field, and give us direction for future bioassay methods.

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Functional Implications of O-GlcNAcylation-dependent Phosphorylation at a Proximal Site on Keratin 18

Cited by 20 publications

References 59 publications

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

The focal adhesion scaffold protein Hic-5 regulates vimentin organization in fibroblasts

Overview of the Assays to Probe O-Linked β-N-Acetylglucosamine Transferase Binding and Activity

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