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Article ; Online: Ubiquitinomics: History, methods, and applications in basic research and drug discovery.

Steger, Martin / Karayel, Özge / Demichev, Vadim

2022 Volume 22, Issue 15-16, Page(s) e2200074

Abstract: The ubiquitin-proteasome system (UPS) was discovered about 40 years ago and is known to regulate a multitude of cellular processes including protein homeostasis. Ubiquitylated proteins are recognized by downstream effectors, resulting in alterations of ... ...

Abstract	The ubiquitin-proteasome system (UPS) was discovered about 40 years ago and is known to regulate a multitude of cellular processes including protein homeostasis. Ubiquitylated proteins are recognized by downstream effectors, resulting in alterations of protein abundance, activity, or localization. Not surprisingly, the ubiquitylation machinery is dysregulated in numerous diseases, including cancers and neurodegeneration. Mass spectrometry (MS)-based proteomics has emerged as a transformative technology for characterizing protein ubiquitylation in an unbiased fashion. Here, we provide an overview of the different MS-based approaches for studying protein ubiquitylation. We review various methods for enriching and quantifying ubiquitin modifications at the peptide or protein level, outline MS acquisition, and data processing approaches and discuss key challenges. Finally, we examine how MS-based ubiquitinomics can aid both basic biology and drug discovery research.
MeSH term(s)	Drug Discovery ; Proteasome Endopeptidase Complex/metabolism ; Proteomics/methods ; Ubiquitin/metabolism ; Ubiquitination
Chemical Substances	Ubiquitin ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2022-05-11
Publishing country	Germany
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2032093-0
ISSN	1615-9861 ; 1615-9853
ISSN (online)	1615-9861
ISSN	1615-9853
DOI	10.1002/pmic.202200074
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Article ; Online: Mitochondrial phosphoproteomes are functionally specialized across tissues.

Hansen, Fynn M / Kremer, Laura S / Karayel, Ozge / Bludau, Isabell / Larsson, Nils-Göran / Kühl, Inge / Mann, Matthias

Life science alliance

2023 Volume 7, Issue 2

Abstract: Mitochondria are essential organelles whose dysfunction causes human pathologies that often manifest in a tissue-specific manner. Accordingly, mitochondrial fitness depends on versatile proteomes specialized to meet diverse tissue-specific requirements. ... ...

Abstract	Mitochondria are essential organelles whose dysfunction causes human pathologies that often manifest in a tissue-specific manner. Accordingly, mitochondrial fitness depends on versatile proteomes specialized to meet diverse tissue-specific requirements. Increasing evidence suggests that phosphorylation may play an important role in regulating tissue-specific mitochondrial functions and pathophysiology. Building on recent advances in mass spectrometry (MS)-based proteomics, we here quantitatively profile mitochondrial tissue proteomes along with their matching phosphoproteomes. We isolated mitochondria from mouse heart, skeletal muscle, brown adipose tissue, kidney, liver, brain, and spleen by differential centrifugation followed by separation on Percoll gradients and performed high-resolution MS analysis of the proteomes and phosphoproteomes. This in-depth map substantially quantifies known and predicted mitochondrial proteins and provides a resource of core and tissue-specific mitochondrial proteins (mitophos.de). Predicting kinase substrate associations for different mitochondrial compartments indicates tissue-specific regulation at the phosphoproteome level. Illustrating the functional value of our resource, we reproduce mitochondrial phosphorylation events on dynamin-related protein 1 responsible for its mitochondrial recruitment and fission initiation and describe phosphorylation clusters on MIGA2 linked to mitochondrial fusion.
MeSH term(s)	Mice ; Animals ; Humans ; Proteome/metabolism ; Mitochondria/metabolism ; Phosphorylation ; Mass Spectrometry ; Mitochondrial Proteins/metabolism
Chemical Substances	Proteome ; Mitochondrial Proteins
Language	English
Publishing date	2023-11-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2575-1077
ISSN (online)	2575-1077
DOI	10.26508/lsa.202302147
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Article ; Online: A GID E3 ligase assembly ubiquitinates an Rsp5 E3 adaptor and regulates plasma membrane transporters.

Langlois, Christine R / Beier, Viola / Karayel, Ozge / Chrustowicz, Jakub / Sherpa, Dawafuti / Mann, Matthias / Schulman, Brenda A

EMBO reports

2022 Volume 23, Issue 6, Page(s) e53835

Abstract: Cells rapidly remodel their proteomes to align their cellular metabolism to environmental conditions. Ubiquitin E3 ligases enable this response, by facilitating rapid and reversible changes to protein stability, localization, or interaction partners. In ... ...

Abstract	Cells rapidly remodel their proteomes to align their cellular metabolism to environmental conditions. Ubiquitin E3 ligases enable this response, by facilitating rapid and reversible changes to protein stability, localization, or interaction partners. In Saccharomyces cerevisiae, the GID E3 ligase regulates the switch from gluconeogenic to glycolytic conditions through induction and incorporation of the substrate receptor subunit Gid4, which promotes the degradation of gluconeogenic enzymes. Here, we show an alternative substrate receptor, Gid10, which is induced in response to changes in temperature, osmolarity, and nutrient availability, regulates the ART-Rsp5 ubiquitin ligase pathway, a component of plasma membrane quality control. Proteomic studies reveal that the levels of the adaptor protein Art2 are elevated upon GID10 deletion. A crystal structure shows the basis for Gid10-Art2 interactions, and we demonstrate that Gid10 directs a GID E3 ligase complex to ubiquitinate Art2. Our data suggest that the GID E3 ligase affects Art2-dependent amino acid transport. This study reveals GID as a system of E3 ligases with metabolic regulatory functions outside of glycolysis and gluconeogenesis, controlled by distinct stress-specific substrate receptors.
MeSH term(s)	Cell Membrane/metabolism ; Endosomal Sorting Complexes Required for Transport/genetics ; Endosomal Sorting Complexes Required for Transport/metabolism ; Membrane Transport Proteins/genetics ; Membrane Transport Proteins/metabolism ; Proteomics ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Ubiquitin/metabolism ; Ubiquitin-Conjugating Enzymes/genetics ; Ubiquitin-Conjugating Enzymes/metabolism ; Ubiquitin-Protein Ligase Complexes/genetics ; Ubiquitin-Protein Ligase Complexes/metabolism ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination
Chemical Substances	Endosomal Sorting Complexes Required for Transport ; Membrane Transport Proteins ; Saccharomyces cerevisiae Proteins ; Ubiquitin ; Ubiquitin-Conjugating Enzymes (EC 2.3.2.23) ; Ubiquitin-Protein Ligase Complexes (EC 2.3.2.23) ; ubiquitin-conjugating enzyme UBC8 (EC 2.3.2.23) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; RSP5 protein, S cerevisiae (EC 6.3.2.-)
Language	English
Publishing date	2022-04-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2020896-0
ISSN	1469-3178 ; 1469-221X
ISSN (online)	1469-3178
ISSN	1469-221X
DOI	10.15252/embr.202153835
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Article: A20 and ABIN-1 cooperate in balancing CBM complex-triggered NF-κB signaling in activated T cells

Yin, Hongli / Karayel, Ozge / Chao, Ying-Yin / Seeholzer, Thomas / Hamp, Isabel / Plettenburg, Oliver / Gehring, Torben / Zielinski, Christina / Mann, Matthias / Krappmann, Daniel

Cellular and molecular life sciences. 2022 Feb., v. 79, no. 2

2022

Abstract: T cell activation initiates protective adaptive immunity, but counterbalancing mechanisms are critical to prevent overshooting responses and to maintain immune homeostasis. The CARD11-BCL10-MALT1 (CBM) complex bridges T cell receptor engagement to NF-κB ... ...

Abstract	T cell activation initiates protective adaptive immunity, but counterbalancing mechanisms are critical to prevent overshooting responses and to maintain immune homeostasis. The CARD11-BCL10-MALT1 (CBM) complex bridges T cell receptor engagement to NF-κB signaling and MALT1 protease activation. Here, we show that ABIN-1 is modulating the suppressive function of A20 in T cells. Using quantitative mass spectrometry, we identified ABIN-1 as an interactor of the CBM signalosome in activated T cells. A20 and ABIN-1 counteract inducible activation of human primary CD4 and Jurkat T cells. While A20 overexpression is able to silence CBM complex-triggered NF-κB and MALT1 protease activation independent of ABIN-1, the negative regulatory function of ABIN-1 depends on A20. The suppressive function of A20 in T cells relies on ubiquitin binding through the C-terminal zinc finger (ZnF)4/7 motifs, but does not involve the deubiquitinating activity of the OTU domain. Our mechanistic studies reveal that the A20/ABIN-1 module is recruited to the CBM complex via A20 ZnF4/7 and that proteasomal degradation of A20 and ABIN-1 releases the CBM complex from the negative impact of both regulators. Ubiquitin binding to A20 ZnF4/7 promotes destructive K48-polyubiquitination to itself and to ABIN-1. Further, after prolonged T cell stimulation, ABIN-1 antagonizes MALT1-catalyzed cleavage of re-synthesized A20 and thereby diminishes sustained CBM complex signaling. Taken together, interdependent post-translational mechanisms are tightly controlling expression and activity of the A20/ABIN-1 silencing module and the cooperative action of both negative regulators is critical to balance CBM complex signaling and T cell activation.
Keywords	T-lymphocytes ; adaptive immunity ; homeostasis ; humans ; mass spectrometry ; proteinases ; signalosome ; ubiquitin ; zinc finger motif
Language	English
Dates of publication	2022-02
Size	p. 112.
Publishing place	Springer International Publishing
Document type	Article
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-022-04154-z
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Article ; Online: Quantitative multiorgan proteomics of fatal COVID-19 uncovers tissue-specific effects beyond inflammation.

Schweizer, Lisa / Schaller, Tina / Zwiebel, Maximilian / Karayel, Özge / Müller-Reif, Johannes Bruno / Zeng, Wen-Feng / Dintner, Sebastian / Nordmann, Thierry M / Hirschbühl, Klaus / Märkl, Bruno / Claus, Rainer / Mann, Matthias

EMBO molecular medicine

2023 Volume 15, Issue 9, Page(s) e17459

Abstract: SARS-CoV-2 may directly and indirectly damage lung tissue and other host organs, but there are few system-wide, untargeted studies of these effects on the human body. Here, we developed a parallelized mass spectrometry (MS) proteomics workflow enabling ... ...

Abstract	SARS-CoV-2 may directly and indirectly damage lung tissue and other host organs, but there are few system-wide, untargeted studies of these effects on the human body. Here, we developed a parallelized mass spectrometry (MS) proteomics workflow enabling the rapid, quantitative analysis of hundreds of virus-infected FFPE tissues. The first layer of response to SARS-CoV-2 in all tissues was dominated by circulating inflammatory molecules. Beyond systemic inflammation, we differentiated between systemic and true tissue-specific effects to reflect distinct COVID-19-associated damage patterns. Proteomic changes in the lungs resembled those of diffuse alveolar damage (DAD) in non-COVID-19 patients. Extensive organ-specific changes were also evident in the kidneys, liver, and lymphatic and vascular systems. Secondary inflammatory effects in the brain were related to rearrangements in neurotransmitter receptors and myelin degradation. These MS-proteomics-derived results contribute substantially to our understanding of COVID-19 pathomechanisms and suggest strategies for organ-specific therapeutic interventions.
MeSH term(s)	Humans ; COVID-19 ; SARS-CoV-2 ; Proteomics ; Inflammation ; Lung
Language	English
Publishing date	2023-07-31
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2467145-9
ISSN	1757-4684 ; 1757-4676
ISSN (online)	1757-4684
ISSN	1757-4676
DOI	10.15252/emmm.202317459
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Article ; Online: DIA-based systems biology approach unveils E3 ubiquitin ligase-dependent responses to a metabolic shift.

Karayel, Ozge / Michaelis, André C / Mann, Matthias / Schulman, Brenda A / Langlois, Christine R

Proceedings of the National Academy of Sciences of the United States of America

2020 Volume 117, Issue 51, Page(s) 32806–32815

Abstract: ... The ... ...

Abstract	The yeast
MeSH term(s)	Carbon/metabolism ; Culture Media ; Fructose-Bisphosphatase/metabolism ; Glucose/metabolism ; Malate Dehydrogenase/metabolism ; Mass Spectrometry/methods ; Point Mutation ; Pyruvate Decarboxylase/metabolism ; Saccharomyces cerevisiae/growth & development ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Sodium-Potassium-Exchanging ATPase/metabolism ; Stress, Physiological ; Systems Biology/methods ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism ; Workflow
Chemical Substances	Culture Media ; ENA1 protein, S cerevisiae ; Saccharomyces cerevisiae Proteins ; Carbon (7440-44-0) ; MDH2 protein, S cerevisiae (EC 1.1.1.37) ; Malate Dehydrogenase (EC 1.1.1.37) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; FBP1 protein, S cerevisiae (EC 3.1.3.11) ; Fructose-Bisphosphatase (EC 3.1.3.11) ; ARO10 protein, S cerevisiae (EC 4.1.1.1) ; Pyruvate Decarboxylase (EC 4.1.1.1) ; Sodium-Potassium-Exchanging ATPase (EC 7.2.2.13) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2020-12-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2020197117
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Article ; Online: High-throughput and high-sensitivity phosphoproteomics with the EasyPhos platform.

Humphrey, Sean J / Karayel, Ozge / James, David E / Mann, Matthias

Nature protocols

2018 Volume 13, Issue 9, Page(s) 1897–1916

Abstract: Mass spectrometry has transformed the field of cell signaling by enabling global studies of dynamic protein phosphorylation ('phosphoproteomics'). Recent developments are enabling increasingly sophisticated phosphoproteomics studies, but practical ... ...

Abstract	Mass spectrometry has transformed the field of cell signaling by enabling global studies of dynamic protein phosphorylation ('phosphoproteomics'). Recent developments are enabling increasingly sophisticated phosphoproteomics studies, but practical challenges remain. The EasyPhos workflow addresses these and is sufficiently streamlined to enable the analysis of hundreds of phosphoproteomes at a depth of >10,000 quantified phosphorylation sites. Here we present a detailed and updated workflow that further ensures high performance in sample-limited conditions while also reducing sample preparation time. By eliminating protein precipitation steps and performing the entire protocol, including digestion, in a single 96-well plate, we now greatly minimize opportunities for sample loss and variability. This results in very high reproducibility and a small sample size requirement (≤200 μg of protein starting material). After cell culture or tissue collection, the protocol takes 1 d, whereas mass spectrometry measurements require ~1 h per sample. Applied to glioblastoma cells acutely treated with epidermal growth factor (EGF), EasyPhos quantified 20,132 distinct phosphopeptides from 200 μg of protein in less than 1 d of measurement time, revealing thousands of EGF-regulated phosphorylation events.
MeSH term(s)	Cell Line, Tumor ; Humans ; Mass Spectrometry/methods ; Phosphoproteins/analysis ; Proteome/analysis ; Proteomics/methods
Chemical Substances	Phosphoproteins ; Proteome
Language	English
Publishing date	2018-09-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2244966-8
ISSN	1750-2799 ; 1754-2189
ISSN (online)	1750-2799
ISSN	1754-2189
DOI	10.1038/s41596-018-0014-9
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Article ; Online: Data-independent acquisition method for ubiquitinome analysis reveals regulation of circadian biology.

Hansen, Fynn M / Tanzer, Maria C / Brüning, Franziska / Bludau, Isabell / Stafford, Che / Schulman, Brenda A / Robles, Maria S / Karayel, Ozge / Mann, Matthias

Nature communications

2021 Volume 12, Issue 1, Page(s) 254

Abstract: Protein ubiquitination is involved in virtually all cellular processes. Enrichment strategies employing antibodies targeting ubiquitin-derived diGly remnants combined with mass spectrometry (MS) have enabled investigations of ubiquitin signaling at a ... ...

Abstract	Protein ubiquitination is involved in virtually all cellular processes. Enrichment strategies employing antibodies targeting ubiquitin-derived diGly remnants combined with mass spectrometry (MS) have enabled investigations of ubiquitin signaling at a large scale. However, so far the power of data independent acquisition (DIA) with regards to sensitivity in single run analysis and data completeness have not yet been explored. Here, we develop a sensitive workflow combining diGly antibody-based enrichment and optimized Orbitrap-based DIA with comprehensive spectral libraries together containing more than 90,000 diGly peptides. This approach identifies 35,000 diGly peptides in single measurements of proteasome inhibitor-treated cells - double the number and quantitative accuracy of data dependent acquisition. Applied to TNF signaling, the workflow comprehensively captures known sites while adding many novel ones. An in-depth, systems-wide investigation of ubiquitination across the circadian cycle uncovers hundreds of cycling ubiquitination sites and dozens of cycling ubiquitin clusters within individual membrane protein receptors and transporters, highlighting new connections between metabolism and circadian regulation.
MeSH term(s)	Circadian Rhythm/physiology ; HEK293 Cells ; Humans ; Peptide Library ; Proteome/metabolism ; Proteomics ; Reproducibility of Results ; Signal Transduction ; Tumor Necrosis Factor-alpha/metabolism ; Ubiquitin/metabolism ; Ubiquitination
Chemical Substances	Peptide Library ; Proteome ; Tumor Necrosis Factor-alpha ; Ubiquitin
Language	English
Publishing date	2021-01-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-020-20509-1
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Article ; Online: Urinary proteome profiling for stratifying patients with familial Parkinson's disease.

Virreira Winter, Sebastian / Karayel, Ozge / Strauss, Maximilian T / Padmanabhan, Shalini / Surface, Matthew / Merchant, Kalpana / Alcalay, Roy N / Mann, Matthias

EMBO molecular medicine

2021 Volume 13, Issue 3, Page(s) e13257

Abstract: The prevalence of Parkinson's disease (PD) is increasing but the development of novel treatment strategies and therapeutics altering the course of the disease would benefit from specific, sensitive, and non-invasive biomarkers to detect PD early. Here, ... ...

Abstract	The prevalence of Parkinson's disease (PD) is increasing but the development of novel treatment strategies and therapeutics altering the course of the disease would benefit from specific, sensitive, and non-invasive biomarkers to detect PD early. Here, we describe a scalable and sensitive mass spectrometry (MS)-based proteomic workflow for urinary proteome profiling. Our workflow enabled the reproducible quantification of more than 2,000 proteins in more than 200 urine samples using minimal volumes from two independent patient cohorts. The urinary proteome was significantly different between PD patients and healthy controls, as well as between LRRK2 G2019S carriers and non-carriers in both cohorts. Interestingly, our data revealed lysosomal dysregulation in individuals with the LRRK2 G2019S mutation. When combined with machine learning, the urinary proteome data alone were sufficient to classify mutation status and disease manifestation in mutation carriers remarkably well, identifying VGF, ENPEP, and other PD-associated proteins as the most discriminating features. Taken together, our results validate urinary proteomics as a valuable strategy for biomarker discovery and patient stratification in PD.
MeSH term(s)	Heterozygote ; Humans ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics ; Mutation ; Parkinson Disease/diagnosis ; Parkinson Disease/genetics ; Proteome ; Proteomics
Chemical Substances	Proteome ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (EC 2.7.11.1)
Language	English
Publishing date	2021-01-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2467145-9
ISSN	1757-4684 ; 1757-4676
ISSN (online)	1757-4684
ISSN	1757-4676
DOI	10.15252/emmm.202013257
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Article ; Online: Multisite phosphorylation dictates selective E2-E3 pairing as revealed by Ubc8/UBE2H-GID/CTLH assemblies.

Chrustowicz, Jakub / Sherpa, Dawafuti / Li, Jerry / Langlois, Christine R / Papadopoulou, Eleftheria C / Vu, D Tung / Hehl, Laura A / Karayel, Özge / Beier, Viola / von Gronau, Susanne / Müller, Judith / Prabu, J Rajan / Mann, Matthias / Kleiger, Gary / Alpi, Arno F / Schulman, Brenda A

Molecular cell

2023 Volume 84, Issue 2, Page(s) 293–308.e14

Abstract: Ubiquitylation is catalyzed by coordinated actions of E3 and E2 enzymes. Molecular principles governing many important E3-E2 partnerships remain unknown, including those for RING-family GID/CTLH E3 ubiquitin ligases and their dedicated E2, Ubc8/UBE2H ( ... ...

Abstract	Ubiquitylation is catalyzed by coordinated actions of E3 and E2 enzymes. Molecular principles governing many important E3-E2 partnerships remain unknown, including those for RING-family GID/CTLH E3 ubiquitin ligases and their dedicated E2, Ubc8/UBE2H (yeast/human nomenclature). GID/CTLH-Ubc8/UBE2H-mediated ubiquitylation regulates biological processes ranging from yeast metabolic signaling to human development. Here, cryoelectron microscopy (cryo-EM), biochemistry, and cell biology reveal this exquisitely specific E3-E2 pairing through an unconventional catalytic assembly and auxiliary interactions 70-100 Å away, mediated by E2 multisite phosphorylation. Rather than dynamic polyelectrostatic interactions reported for other ubiquitylation complexes, multiple Ubc8/UBE2H phosphorylation sites within acidic CK2-targeted sequences specifically anchor the E2 C termini to E3 basic patches. Positions of phospho-dependent interactions relative to the catalytic domains correlate across evolution. Overall, our data show that phosphorylation-dependent multivalency establishes a specific E3-E2 partnership, is antagonistic with dephosphorylation, rigidifies the catalytic centers within a flexing GID E3-substrate assembly, and facilitates substrate collision with ubiquitylation active sites.
MeSH term(s)	Humans ; Ubiquitin-Conjugating Enzymes/metabolism ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Phosphorylation ; Cryoelectron Microscopy ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination
Chemical Substances	Ubiquitin-Conjugating Enzymes (EC 2.3.2.23) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; UBE2H protein, human (EC 2.3.2.23)
Language	English
Publishing date	2023-12-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2023.11.027
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