scholarly journals The role of USP7 in the Shoc2 - ERK1/2 signaling axis and Noonan-like syndrome with loose anagen hair (NSLAH)

2021 ◽  
Author(s):  
Patricia Wilson ◽  
Lina Abdelmoti ◽  
Rebecca Norcross ◽  
Eun Ryoung Jang ◽  
Malathy Palayam ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Pathway Activation ◽  
Signaling Axis ◽  
Specific Protease ◽  
Anagen Hair ◽  
Ubiquitin Specific Protease ◽  
Regulatory Feedback Loop ◽  
Organismal Development ◽  
Fine Tune

The ERK1/2 signaling pathway is critical in organismal development and tissue morphogenesis. Deregulation of this pathway leads to congenital abnormalities with severe developmental dysmorphisms. The core ERK1/2 cascade relies on scaffold proteins such as Shoc2 to guide and fine-tune its signals. Mutations in shoc2 lead to the development of the pathology termed Noonan-like Syndrome with Loose Anagen Hair (NSLAH). However, the mechanisms underlying the functions of Shoc2 and its contributions to disease progression remain unclear. Here we show that ERK1/2 pathway activation triggers the interaction of Shoc2 with the ubiquitin-specific protease USP7. We identify that in the Shoc2 module USP7 functions as a molecular “switch” that controls the E3 ligase HUWE1 and the HUWE1-induced regulatory feedback loop. We also demonstrate that disruption of Shoc2-USP7 binding leads to aberrant activation of the Shoc2-ERK1/2 axis. Importantly, our studies reveal a possible role for USP7 in the pathogenic mechanisms underlying NSLAH extending our understanding of how ubiquitin-specific proteases regulate intracellular signaling.

scholarly journals Ubiquitin-Specific Protease 25 Aggravates Acute Pancreatitis and Acute Pancreatitis-Related Multiple Organ Injury by Destroying Tight Junctions Through Activation of The STAT3 Pathway

2022 ◽  
Vol 9 ◽  
Author(s):  
Zhengru Liu ◽  
Mingming Qi ◽  
Shan Tian ◽  
Qian Yang ◽  
Jian Liu ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Tight Junctions ◽  
Multiple Organ ◽  
Organ Injury ◽  
Pancreatic Acinar Cells ◽  
Stat3 Pathway ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Multiple Organ Injury

Ubiquitin-specific protease 25 (USP25) plays an important role in inflammation and immunity. However, the role of USP25 in acute pancreatitis (AP) is still unclear. To evaluate the role of USP25 in AP, we conducted research on clinical AP patients, USP25wild-type(WT)/USP25 knockout (USP25−/−) mice, and pancreatic acinar cells. Our results showed that serum USP25 concentration was higher in AP patients than in healthy controls and was positively correlated with disease severity. AP patients’ serum USP25 levels after treatment were significantly lower than that at the onset of AP. Moreover, USP25 expression was upregulated in cerulein-induced AP in mice, while USP25 deficiency attenuates AP and AP-related multiple organ injury. In vivo and in vitro studies showed that USP25 exacerbates AP by promoting the release of pro-inflammatory factors and destroying tight junctions of the pancreas. We showed that USP25 aggravates AP and AP-related multiple organ injury by activating the signal transducer and activator of transcription 3 (STAT3) pathway. Targeting the action of USP25 may present a potential therapeutic option for treating AP.

scholarly journals Ubiquitin-Specific Protease 8 Mutant Corticotrope Adenomas Present Unique Secretory and Molecular Features and Shed Light on the Role of Ubiquitylation on ACTH Processing

2019 ◽  
Vol 110 (1-2) ◽  
pp. 119-129 ◽  
Author(s):  
Antonella Sesta ◽  
Maria Francesca Cassarino ◽  
Mariarosa Terreni ◽  
Alberto G. Ambrogio ◽  
Laura Libera ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Pituitary Adenomas ◽  
Expression Profiles ◽  
Primary Cultures ◽  
Acth Secretion ◽  
Specific Protease ◽  
Ubiquitin Proteasome ◽  
Ubiquitin Specific Protease ◽  
Acth Secreting

Background: Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene have recently been shown to occur in ACTH-secreting pituitary adenomas, thus calling attention to the ubiquitin system in corticotrope adenomas. Objectives: Assess the consequences of USP8 mutations and establish the role of ubiquitin on ACTH turnover in human ACTH-secreting pituitary adenomas. Methods: USP8 mutation status was established in 126 ACTH-secreting adenomas. Differences in ACTH secretion and POMC expression from adenoma primary cultures and in microarray gene expression profiles from archival specimens were sought according to USP8 sequence. Ubiquitin/ACTH coimmunoprecipitation and incubation with MG132, a proteasome inhibitor, were performed in order to establish whether ubiquitin plays a role in POMC/ACTH degradation in corticotrope adenomas. Results: USP8 mutations were identified in 29 adenomas (23%). Adenomas presenting USP8 mutations secreted greater amounts of ACTH and expressed POMC at higher levels compared to USP wild-type specimens. USP8 mutant adenomas were also more sensitive to modulation by CRH and dexamethasone in vitro. At microarray analysis, genes associated with endosomal protein degradation and membrane components were downregulated in USP8 mutant adenomas as were AVPR1B, IL11RA, and PITX2. Inhibition of the ubiquitin-proteasome pathway increased ACTH secretion and POMC itself proved a target of ubiquitylation, independently of USP8 sequence status. Conclusions: Our study has shown that USP8 mutant ACTH-secreting adenomas present a more “typical” corticotrope phenotype and reduced expression of several genes associated with protein degradation. Further, ubiquitylation is directly involved in intracellular ACTH turnover, suggesting that the ubiquitin-proteasome system may represent a target for treatment of human ACTH-secreting adenomas.

scholarly journals The targetable role of herpes virus-associated ubiquitin-specific protease (HAUSP) in p190 BCR-ABL leukemia

2016 ◽  
Vol 12 (5) ◽  
pp. 3123-3126 ◽  
Author(s):  
Giovanna Carrà ◽  
Cristina Panuzzo ◽  
Sabrina Crivellaro ◽  
Deborah Morena ◽  
Riccardo Taulli ◽  
...  
Keyword(s):  
Herpes Virus ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Herpès Virus

Proteomics analysis reveals the role of ubiquitin specific protease (USP47) in Epithelial to Mesenchymal Transition (EMT) induced by TGFβ2 in breast cells

2020 ◽  
Vol 219 ◽  
pp. 103734 ◽  
Author(s):  
Virgínia Campos Silvestrini ◽  
Carolina Hassibe Thomé ◽  
Daniele Albuquerque ◽  
Camila de Souza Palma ◽  
Germano Aguiar Ferreira ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Proteomics Analysis ◽  
Mesenchymal Transition ◽  
Specific Protease ◽  
Breast Cells ◽  
Ubiquitin Specific Protease

EXPRESSION AND ROLE OF TYPE 1 AND 2 ISOFORMS OF UBIQUITIN-SPECIFIC PROTEASE 14 IN HUMAN PANCREATIC CANCER

Pancreas ◽  
2006 ◽  
Vol 33 (4) ◽  
pp. 471
Author(s):  
T. Ishiwata ◽  
K. Cho ◽  
S. Ishiwata ◽  
Y. Fujiwata ◽  
T. Fujii ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Human Pancreatic Cancer ◽  
Specific Protease ◽  
Ubiquitin Specific Protease

scholarly journals Allosteric switch regulates protein–protein binding through collective motion

2016 ◽  
Vol 113 (12) ◽  
pp. 3269-3274 ◽  
Author(s):  
Colin A. Smith ◽  
David Ban ◽  
Supriya Pratihar ◽  
Karin Giller ◽  
Maria Paulat ◽  
...  
Keyword(s):  
Collective Motion ◽  
Protein Domain ◽  
Allosteric Coupling ◽  
Allosteric Communication ◽  
Binding Interface ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Promising Avenue

Many biological processes depend on allosteric communication between different parts of a protein, but the role of internal protein motion in propagating signals through the structure remains largely unknown. Through an experimental and computational analysis of the ground state dynamics in ubiquitin, we identify a collective global motion that is specifically linked to a conformational switch distant from the binding interface. This allosteric coupling is also present in crystal structures and is found to facilitate multispecificity, particularly binding to the ubiquitin-specific protease (USP) family of deubiquitinases. The collective motion that enables this allosteric communication does not affect binding through localized changes but, instead, depends on expansion and contraction of the entire protein domain. The characterization of these collective motions represents a promising avenue for finding and manipulating allosteric networks.

scholarly journals Proinflammatory Effects of Ubiquitin-Specific Protease 5 (USP5) in Rheumatoid Arthritis Fibroblast-Like Synoviocytes

2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Xiao-Bo Luo ◽  
Jian-Cheng Xi ◽  
Zhen Liu ◽  
Yu Long ◽  
Li-tao Li ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Tumor Necrosis Factor Receptor ◽  
Dependent Manner ◽  
Autoimmune Inflammatory Disease ◽  
Specific Protease ◽  
Inflammatory Processes ◽  
Ubiquitin Specific Protease ◽  
Signaling Activation ◽  
Fibroblast Like Synoviocytes

Rheumatoid arthritis (RA) is a worldwide chronic autoimmune inflammatory disease which is affecting approximately 1% of the total population. It is characterized by abnormal proliferation of fibroblast-like synoviocytes (FLS) and increased production of proinflammatory cytokines. In the current study, we were aiming to investigate the role of ubiquitin-specific protease 5 (USP5) in the inflammatory process in RA-FLS. Expression of USP5 was found upregulated in RA-FLS compared with that in osteoarthritis- (OA-) FLS, and IL-1β stimulation increased USP5 expression in a time-dependent manner. Furthermore, we found that USP5 overexpression significantly aggravated proinflammatory cytokine production and related nuclear factor κB (NF-κB) signaling activation. Consistently, silencing of USP5 decreased the release of cytokines and inhibited the activation of NF-κB. In addition, USP5 was found to interact with tumor necrosis factor receptor-associated factor 6 (TRAF6) and remove its K48-linked polyubiquitination chains therefore stabilizing TRAF6. Our data showed that a USP5-positive cell regulates inflammatory processes in RA-FLS and suggested USP5 as a potential target for RA treatment.

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