Large-Scale Quantitative Proteomics Identifies the Ubiquitin Ligase Nedd4-1 as an Essential Regulator of Liver Regeneration

Bachofner, Marc; Speicher, Tobias; Bogorad, Roman L.; Muzumdar, Sukalp; Derrer, Carina Patrizia; Hürlimann, Fabrizio; Böhm, Friederike; Nanni, Paolo; Kockmann, Tobias; Kachaylo, Ekaterina; Meyer, Michaël; Padrissa-Altés, Susagna; Graf, Rolf; Anderson, Daniel G.; Koteliansky, Victor; Keller, Ulrich auf dem; Werner, Sabine

doi:10.1016/j.devcel.2017.07.025

Cited by 26 publications

(22 citation statements)

References 52 publications

(72 reference statements)

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“…This method outperforms the standard t statistics (38) as it reduces the sample variance toward an estimated value, based on the average protein variance. This analysis, yielded a short list of differentially expressed proteins that were chosen based on adjusted p values, using the False Discovery Rate (FDR) as demonstrated by Bachofner & colleagues (43). To gain more confidence on this preliminary screen, this protein list was compared with previously identified Cts B and L targets (Venn diagram).…”

Section: Methodsmentioning

confidence: 99%

Cathepsin L Regulates Metabolic Networks Controlling Rapid Cell Growth and Proliferation

Weiss-Sadan

Itzhak

Kaschani

et al. 2019

Molecular & Cellular Proteomics

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Remodeling of cellular metabolism is a genuine feature of rapidly growing cells. Herein we report that mouse embryonic fibroblasts, lacking the Cathepsin L (Cts L) gene, proliferate faster than wild-types and display a noticeable glycolytic shift to satisfy their ever-growing metabolic needs. Mass spectrometry analyses identified LDHA as an essential metabolic junction in these cells, and downstream biochemical studies suggested that Cts L regulates LDHA expression and function. Together, these data uncover an unprecedented role for Cathepsin L in cell metabolism.

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Section: Methodsmentioning

confidence: 99%

Cathepsin L Regulates Metabolic Networks Controlling Rapid Cell Growth and Proliferation

Weiss-Sadan

Itzhak

Kaschani

et al. 2019

Molecular & Cellular Proteomics

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“…Therefore, AHD is considered a pre-ACLF condition, and the prognoses for AHD and ACLF differ considerably (2, 10). The emergence of quantitative proteomics technologies has facilitated the high-throughput discovery of candidate biomarkers, particularly noninvasive blood biomarkers, of liver pathophysiology such as those for liver regeneration (11), hepatocyte differentiation and dedifferentiation (12), and acute injury and failure (13,14). However, few studies have focused on biomarkers distinguishing ACLF from AHD, or ACLF survivors from nonsurvivors.…”

Section: Introductionmentioning

confidence: 99%

Plasminogen as a prognostic biomarker for HBV-related acute-on-chronic liver failure

Wu¹,

Zhang²,

Xie³

et al. 2020

Journal of Clinical Investigation

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viduals infected with HBV worldwide (4). In most Asian countries, HBV-related ACLF (HBV-ACLF) accounts for over 70% of ACLF cases (5, 6). Reports have shown that the patient's condition at admission is linked to the outcome of ACLF (1, 7); thus, biomarkers that enable early and accurate risk stratification are needed. Additionally, ACLF is a highly dynamic process; therefore, sequential assessments of biomarkers that reflect the course of liver failure during hospitalization may enhance the management of patients with ACLF (7-9). However, to our knowledge, no biomarker has satisfactorily addressed these challenges. Patients with CLD who experience an episode of acute hepatic insult causing liver dysfunction are considered to have acute BACKGROUND. HBV-related acute-on-chronic liver failure (HBV-ACLF) is hallmarked by high short-term mortality rates, calling for accurate prognostic biomarkers for initial risk stratification. METHODS. Three tandem mass tag-labeled (TMT-labeled) quantitative proteomic studies were performed on 10 patients with HBV-related acute hepatic decompensation and on 20 patients with HBV-ACLF. Candidate biomarkers were preliminarily verified in a cross-sectional cohort (n = 144) and further confirmed in 2 prospective cohorts (n = 207 and n = 148). RESULTS. Plasminogen, a potential prognostic biomarker for HBV-ACLF, was identified by TMT quantitative proteomics and preliminarily verified in the cross-sectional cohort. Further validation with a prospective cohort (n = 207) showed that plasminogen levels at admission were significantly lower (P < 0.001) in HBV-ACLF nonsurvivors than in survivors. The cumulative survival duration of patients with high plasminogen levels was significantly longer (P < 0.001) than that of patients with low plasminogen levels. During hospitalization, plasminogen levels significantly decreased (P = 0.008) in the deterioration group but significantly increased (P < 0.001) in the improvement group. Additionally, plasminogen levels gradually increased in survivors but gradually decreased in nonsurvivors. The P5 score, a prognostic panel incorporating plasminogen levels, hepatic encephalopathy occurrence, age, international normalized ratio (INR), and total bilirubin, was significantly superior to the Child-Pugh, Model for End-stage Liver Disease (MELD), Chronic Liver Failure Consortium ACLF (CLIF-C ACLF), Chinese Group on the Study of Severe Hepatitis B (COSSH), and HINT (a prognostic score based on hepatic encephalopathy occurrence, INR, neutrophil count, and thyroid-stimulating hormone) scores (all P < 0.05). The performances of the plasminogen level and P5 score were validated in a second multicenter, prospective cohort (n = 148). CONCLUSIONS. Plasminogen is a promising prognostic biomarker for HBV-ACLF, and sequential plasminogen measurements could profile the clinical course of HBV-ACLF. P5 is a high-performance prognostic score for HBV-ACLF.

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“…www.nature.com/scientificreports www.nature.com/scientificreports/ recent study demonstrates highly enriched ubiquitination/proteasomal degradation in liver regeneration, especially NEDD4 as an essential regulator by performing EPS15 ubiquitination which promotes EGFR internalization and efficient signaling in hepatocytes 21 . We were able to detect EGFR and EPS15 after wounding with a 2.7-fold increased NEDD4 at day7 in Acomys but EGFR and NEDD4 were either constant or significantly decreased in Mus, with little EPS15.…”

Section: Discussionmentioning

confidence: 99%

Comparative Proteomic Analysis in Scar-Free Skin Regeneration in Acomys cahirinus and Scarring Mus musculus

Yoon

Cho

Garrett

et al. 2020

Sci Rep

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The spiny mouse, Acomys cahirinus displays a unique wound healing ability with regeneration of all skin components in a scar-free manner. To identify orchestrators of this regenerative response we have performed proteomic analyses of skin from Acomys and Mus musculus before and after wounding. Of the ~2000 proteins identified many are expressed at similar levels in Acomys and Mus, but there are significant differences. Following wounding in Mus the complement and coagulation cascades, PPAR signaling pathway and ECM-receptor interactions predominate. In Acomys, other pathways predominate including the Wnt, MAPK, the ribosome, proteasome, endocytosis and tight junction pathways. Notable among Acomys specific proteins are several ubiquitin-associated enzymes and kinases, whereas in Mus immuno-modulation proteins characteristic of inflammatory response are unique or more prominent. ECM proteins such as collagens are more highly expressed in Mus, but likely more important is the higher expression of matrix remodeling proteases in Acomys. Another distinctive difference between Acomys and Mus lies in the macrophage-produced arginase 1 is found in Mus whereas arginase 2 is found in Acomys. Thus, we have identified several avenues for experimental approaches whose aim is to reduce the fibrotic response that the typical mammal displays in response to wounding.

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Large-Scale Quantitative Proteomics Identifies the Ubiquitin Ligase Nedd4-1 as an Essential Regulator of Liver Regeneration

Cited by 26 publications

References 52 publications

Cathepsin L Regulates Metabolic Networks Controlling Rapid Cell Growth and Proliferation

Cathepsin L Regulates Metabolic Networks Controlling Rapid Cell Growth and Proliferation

Plasminogen as a prognostic biomarker for HBV-related acute-on-chronic liver failure

Comparative Proteomic Analysis in Scar-Free Skin Regeneration in Acomys cahirinus and Scarring Mus musculus

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