UbiSite approach for comprehensive mapping of lysine and N-terminal ubiquitination sites

Akimov, Vyacheslav; Barrio-Hernandez, Iñigo; Hansen, Sten V F; Hallenborg, Philip; Pedersen, Anna-Kathrine; Bekker-Jensen, Dorte B.; Puglia, Michele; Christensen, Stine Duelund Kaas; Vanselow, Jens T.; Nielsen, Mogens M.; Kratchmarova, Irina; Kelstrup, Christian D.; Olsen, Jesper V.; Blagoev, Blagoy

doi:10.1038/s41594-018-0084-y

Cited by 347 publications

(340 citation statements)

References 69 publications

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“…Next, we demonstrated that LUZP1 is ubiquitinated, and that truncated SALL1 both increases LUZP1 ubiquitination and decreases its stability. LUZP1 ubiquitination was detected in several proteomic screens for ubiquitinated proteins (47–51). The mechanism by which truncated SALL1 can influence LUZP1 ubiquitination is yet to be revealed, but one possibility could be de novo complexes involving specific Ub E3 ligases or de-ubiquitinases which could influence LUZP1 stability.…”

Section: Discussionmentioning

confidence: 99%

LUZP1, a novel regulator of primary cilia and the actin cytoskeleton, is altered in Townes-Brocks Syndrome

Bozal-Basterra

Gonzalez-Santamarta

Bermejo-Arteagabeitia

et al. 2019

Preprint

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36Primary cilia are sensory organelles that are crucial for cell signaling during 37 development and organ homeostasis. Cilia arise from the centrosome and their 38 formation is governed by numerous regulatory factors. We show that the leucine-zipper 39 protein LUZP1 localizes to the pericentriolar material and actin cytoskeleton. Using 40TurboID proximity labeling and pulldowns, LUZP1 associates with factors linked to 41 centrosome and actin filaments. Loss of LUZP1 reduces F-actin levels, facilitating 42 ciliogenesis and altering Sonic Hedgehog signaling, pointing to a key role in the 43 cytoskeleton-cilia interdependency. Moreover, we show that LUZP1 interacts with a 44 truncated form of the transcription factor SALL1 that causes Townes-Brocks Syndrome. 45 TBS is characterized by digit, heart and kidney malformations and is linked in part to 46 defective cilia. Truncated SALL1 increases the ubiquitin proteasome-mediated 47 51Primary cilia are sensory organelles that have a crucial role in cell signaling, 52 polarity and protein trafficking during development and organ homeostasis. 53 Importantly, the involvement of primary cilia in the above-mentioned processes is 54 frequently due to its role in Sonic Hedgehog (Shh) pathway regulation (1). Briefly, Shh 55 activation through its receptor PTCH1 leads to ciliary enrichment of the transmembrane 56 protein Smoothened (SMO), with concomitant conversion of the transcription factor 57 GLI3 from a cleaved repressor form to a full-length activator form, leading to activation 58 of Shh target genes. Two such genes are PTCH1 and GLI1 (encoding the Shh receptor 59 and a transcriptional activator, respectively), exemplifying the feedback and fine-tuning 60 of the Shh pathway. 61Cilia arise from the centrosome, a cellular organelle composed of two barrel-62 shaped microtubule-based structures called the centrioles. Primary cilia formation is 63 very dynamic throughout the cell cycle. Cilia are nucleated from the mother centriole 64 (MC) at the membrane-anchored basal body upon entry into the G0 phase, and they 65 reabsorb as cells progress from G1 to S phase, completely disassembling in mitosis (2). 66Centrioles are surrounded by protein-based matrix pericentriolar material (PCM) (3, 4). 67In eukaryotic cells, PCM proteins are concentrically arranged around a centriole in a 68 highly organized manner (5-8). Based on this observation, proper positioning and 69 organization of PCM proteins may be important for promoting different cellular 70 processes in a spatially regulated way (9). Not surprisingly, aberrations in the function 71 of PCM scaffolds are also associated with many human diseases, including cancer and 72 ciliopathies (10, 11). 73Cilia assembly and disassembly are regulated by diverse factors, including the 74 main cilia suppressor proteins CCP110 and CEP97 and the actin cytoskeleton. CCP110 75 4 and CEP97 form a complex that, when removed from the MC, allows ciliogenesis (12). 76The regulation of actin dynamics is also considered a major ciliogenesis driver in 7...

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Section: Discussionmentioning

confidence: 99%

LUZP1, a novel regulator of primary cilia and the actin cytoskeleton, is altered in Townes-Brocks Syndrome

Bozal-Basterra

Gonzalez-Santamarta

Bermejo-Arteagabeitia

et al. 2019

Preprint

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“…Ser2 of the NUCLEOSOME ASSEMBLY PROTEIN1 (NAP1, AT2G19480.1) could be uncovered by N-terminal methionine excision and be N-terminally acetylated (Linster et al, 2015;Zhang et al, 2015Zhang et al, , 2018, phosphorylated (Roitinger et al, 2015) and even N-terminally ubiquitinated (Walton et al, 2016). Although this N-terminal ubiquitination was described for only 10 sites, innovative techniques, such as UbiSite, are bound to detect additional sites in the future (Akimov et al, 2018). Hence, the N-terminal modification landscape of some proteins might be more complex and dynamic than anticipated.…”

Section: Assessment Of the Ptm Interplay With The 'Ptm Search' Toolmentioning

confidence: 99%

The Plant PTM Viewer, a central resource for exploring plant protein modifications

et al. 2019

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Summary Post‐translational modifications (PTMs) of proteins are central in any kind of cellular signaling. Modern mass spectrometry technologies enable comprehensive identification and quantification of various PTMs. Given the increased numbers and types of mapped protein modifications, a database is necessary that simultaneously integrates and compares site‐specific information for different PTMs, especially in plants for which the available PTM data are poorly catalogued. Here, we present the Plant PTM Viewer (http://www.psb.ugent.be/PlantPTMViewer), an integrative PTM resource that comprises approximately 370 000 PTM sites for 19 types of protein modifications in plant proteins from five different species. The Plant PTM Viewer provides the user with a protein sequence overview in which the experimentally evidenced PTMs are highlighted together with an estimate of the confidence by which the modified peptides and, if possible, the actual modification sites were identified and with functional protein domains or active site residues. The PTM sequence search tool can query PTM combinations in specific protein sequences, whereas the PTM BLAST tool searches for modified protein sequences to detect conserved PTMs in homologous sequences. Taken together, these tools help to assume the role and potential interplay of PTMs in specific proteins or within a broader systems biology context. The Plant PTM Viewer is an open repository that allows the submission of mass spectrometry‐based PTM data to remain at pace with future PTM plant studies.

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“…The data from figures and tables in the BioGRID webpage (https://thebiogrid.org/) can be searched and sorted. For post-translational modification detection and delineation of ubiquitination at a site-specific level we used UbiSite webpage (http://csb.cse.yzu.edu.tw/UbiSite/) (Akimov et al, 2018). Murine Tabula Muris open database was used to generate the figures shown in Fig.…”

Section: Methodsmentioning

confidence: 99%

TGF-β-driven downregulation of the Wnt/β-Catenin transcription factor TCF7L2/TCF4 in PDGFRα⁺ fibroblasts

Contreras¹,

Soliman

Théret

et al. 2020

Preprint

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Mesenchymal stromal/stem cells (MSCs) are multipotent progenitors essential ororganogenesis, tissue homeostasis, regeneration, and scar formation. Tissue injury upregulates TGF-β signaling, which modulates myofibroblast fate, extracellular matrix remodeling, and fibrosis. However, the molecular determinants of MSCs differentiation and survival remain poorly understood. The canonical Wnt Tcf/Lef transcription factors regulate development and stemness, but the mechanisms by which injury-induced cues modulate their expression remain underexplored. Here, we studied the cell-specific gene expression of Tcf/Lef and, more specifically, we investigated whether damage-induced TGF-β impairs the expression and function of TCF7L2, using several models of MSCs, including skeletal muscle fibro-adipogenic progenitors. We show that Tcf/Lefs are differentially expressed and that TGF-β reduces the expression of TCF7L2 in MSCs but not in myoblasts. We also found that the ubiquitin-proteasome system regulates TCF7L2 proteostasis and participates in TGF-β-mediated TCF7L2 protein downregulation. Finally, we show that TGF-β requires HDACs activity to repress the expression of TCF7L2. Thus, our work found a novel interplay between TGF-β and Wnt canonical signaling cascades in PDGFRα+ fibroblasts and suggests that this mechanism could be targeted in tissue repa ir and regeneration.Summary statementTGF-β signaling suppresses the expression of the Wnt transcription factor TCF7L2 and compromises TCF7L2-dependent functions in tissue-resident PDGFRα+ fibroblasts.

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UbiSite approach for comprehensive mapping of lysine and N-terminal ubiquitination sites

Cited by 347 publications

References 69 publications

LUZP1, a novel regulator of primary cilia and the actin cytoskeleton, is altered in Townes-Brocks Syndrome

LUZP1, a novel regulator of primary cilia and the actin cytoskeleton, is altered in Townes-Brocks Syndrome

The Plant PTM Viewer, a central resource for exploring plant protein modifications

TGF-β-driven downregulation of the Wnt/β-Catenin transcription factor TCF7L2/TCF4 in PDGFRα⁺ fibroblasts

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UbiSite approach for comprehensive mapping of lysine and N-terminal ubiquitination sites

Cited by 347 publications

References 69 publications

LUZP1, a novel regulator of primary cilia and the actin cytoskeleton, is altered in Townes-Brocks Syndrome

LUZP1, a novel regulator of primary cilia and the actin cytoskeleton, is altered in Townes-Brocks Syndrome

The Plant PTM Viewer, a central resource for exploring plant protein modifications

TGF-β-driven downregulation of the Wnt/β-Catenin transcription factor TCF7L2/TCF4 in PDGFRα+ fibroblasts

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Product

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TGF-β-driven downregulation of the Wnt/β-Catenin transcription factor TCF7L2/TCF4 in PDGFRα⁺ fibroblasts