The role of <scp>SMURFs</scp> in non‐cancerous diseases

Wang, Dong; Zou, Yuanming; Huang, Xinyue; Yin, Zeyu; Li, Mohan; Jiang-tao, XU; Wu, Boquan; Li, Da; Zhang, Ying; Sun, Yingxian; Zhang, Xingang; Zhang, Naijin

doi:10.1096/fj.202300598r

Cited by 5 publications

(4 citation statements)

References 198 publications

(338 reference statements)

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“…The highly similar Smurf1 and Smurf2 proteins belong to the NEDD4 subfamily of HECT E3 ligases and have distinct and overlapping roles in a range of biological processes and diseases (Koganti et al, 2018 ; Wang et al, 2023 ). Intriguingly, within the context of cancer, these proteins appear to have unique roles as either tumor suppressors or oncogenes, with Smurf2 possibly behaving as both depending on context (Fu et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Structural and functional validation of a highly specific Smurf2 inhibitor

Tessier,

Chowdhury,

Stekel

et al. 2024

Protein Science

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Smurf1 and Smurf2 are two closely related members of the HECT (homologous to E6AP carboxy terminus) E3 ubiquitin ligase family and play important roles in the regulation of various cellular processes. Both were initially identified to regulate transforming growth factor‐β and bone morphogenetic protein signaling pathways through regulating Smad protein stability and are now implicated in various pathological processes. Generally, E3 ligases, of which over 800 exist in humans, are ideal targets for inhibition as they determine substrate specificity; however, there are few inhibitors with the ability to precisely target a particular E3 ligase of interest. In this work, we explored a panel of ubiquitin variants (UbVs) that were previously identified to bind Smurf1 or Smurf2. In vitro binding and ubiquitination assays identified a highly specific Smurf2 inhibitor, UbV S2.4, which was able to inhibit ligase activity with high potency in the low nanomolar range. Orthologous cellular assays further demonstrated high specificity of UbV S2.4 towards Smurf2 and no cross‐reactivity towards Smurf1. Structural analysis of UbV S2.4 in complex with Smurf2 revealed its mechanism of inhibition was through targeting the E2 binding site. In summary, we investigated several protein‐based inhibitors of Smurf1 and Smurf2 and identified a highly specific Smurf2 inhibitor that disrupts the E2‐E3 protein interaction interface.This article is protected by copyright. All rights reserved.

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Section: Discussionmentioning

confidence: 99%

Structural and functional validation of a highly specific Smurf2 inhibitor

Tessier,

Chowdhury,

Stekel

et al. 2024

Protein Science

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“…This upregulation, emerging 10 to 15 years before symptom onset and coinciding with increases in Aβ, tau, phospho-tau, and tau PET ndings, offers insights into AD mechanisms. It may re ect a protective response or contribute to AD pathogenesis, possibly in reaction to AD-related in ammation 51,91,92,93 . These ndings necessitate further research to explore these proteins' roles in misfolded protein aggregation and their impact on other degradation systems like autophagy 94 .…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin-Proteasome System in the Different Stages of Dominantly Inherited Alzheimer’s Disease

McDade,

Liu,

Bui

et al. 2024

Preprint

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This study explored the role of the ubiquitin-proteasome system (UPS) in dominantly inherited Alzheimer’s disease (DIAD) by examining changes in cerebrospinal fluid (CSF) levels of UPS proteins along with disease progression, AD imaging biomarkers (PiB PET, tau PET), neurodegeneration imaging measures (MRI, FDG PET), and Clinical Dementia Rating® (CDR®). Using the SOMAscan assay, we detected subtle increases in specific ubiquitin enzymes associated with proteostasis in mutation carriers (MCs) up to two decades before the estimated symptom onset. This was followed by more pronounced elevations of UPS-activating enzymes, including E2 and E3 proteins, and ubiquitin-related modifiers. Our findings also demonstrated consistent correlations between UPS proteins and CSF biomarkers such as Aβ42/40 ratio, total tau, various phosphorylated tau species to total tau ratios (ptau181/T181, ptauT205/T205, ptauS202/S202, ptauT217/T217), and MTBR-tau243, alongside Neurofilament light chain (NfL) and the CDR®. Notably, a positive association was observed with imaging markers (PiB PET, tau PET) and a negative correlation with markers of neurodegeneration (FDG PET, MRI), highlighting a significant link between UPS dysregulation and neurodegenerative processes. The correlations suggest that the increase in multiple UPS proteins with rising tau levels and tau-tangle associated markers, indicating a potential role for the UPS in relation to misfolded tau/neurofibrillary tangles (NFTs) and symptom onset. These findings indicate that elevated CSF UPS proteins in DIAD MCs could serve as early indicators of disease progression and suggest a link between UPS dysregulation and amyloid plaque, tau tangles formation, implicating the UPS as a potential therapeutic target in AD pathogenesis.

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“…108 Smurf2 ubiquitinates SMAD7, a negative regulator of TGFβ (transforming growth factor β) . 109 ACE2 downregulation in hypertensive nephropathy enhances SMAD7 ubiquitination by Smurf2. Mice lacking ACE2 develop hypertensive nephropathy in a more severe way compared with wild-type mice treated with Ang-II.…”

Section: Posttranslational Modifications Of Ace2mentioning

confidence: 99%

Angiotensin-Converting Enzyme 2 Posttranslational Modifications and Implications for Hypertension and SARS-CoV-2: 2023 Lewis K. Dahl Memorial Lecture

Elgazzaz,

Filipeanu,

Lazartigues

2024

Hypertension

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ACE2 (angiotensin-converting enzyme 2), a multifunctional transmembrane protein, is well recognized as an important member of the (RAS) renin–angiotensin system with important roles in the regulation of cardiovascular function by opposing the harmful effects of Ang-II (angiotensin II) and AT1R (Ang-II type 1 receptor) activation. More recently, ACE2 was found to be the entry point for the SARS-CoV-2 virus into cells, causing COVID-19. This finding has led to an exponential rise in the number of publications focused on ACE2, albeit these studies often have opposite objectives to the preservation of ACE2 in cardiovascular regulation. However, notwithstanding accumulating data of the role of ACE2 in the generation of angiotensin-(1–7) and SARS-CoV-2 internalization, numerous other putative roles of this enzyme remain less investigated and not yet characterized. Currently, no drug modulating ACE2 function or expression is available in the clinic, and the development of new pharmacological tools should attempt targeting each step of the lifespan of the protein from synthesis to degradation. The present review expands on our presentation during the 2023 Lewis K. Dahl Memorial Lecture Sponsored by the American Heart Association Council on Hypertension. We provide a critical summary of the current knowledge of the mechanisms controlling ACE2 internalization and intracellular trafficking, the mutual regulation with GPCRs (G-protein–coupled receptors) and other proteins, and posttranslational modifications. A major focus is on ubiquitination which has become a critical step in the modulation of ACE2 cellular levels.

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The role of SMURFs in non‐cancerous diseases

Cited by 5 publications

References 198 publications

Structural and functional validation of a highly specific Smurf2 inhibitor

Structural and functional validation of a highly specific Smurf2 inhibitor

Ubiquitin-Proteasome System in the Different Stages of Dominantly Inherited Alzheimer’s Disease

Angiotensin-Converting Enzyme 2 Posttranslational Modifications and Implications for Hypertension and SARS-CoV-2: 2023 Lewis K. Dahl Memorial Lecture

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