Deubiquitination and Activation of the NLRP3 Inflammasome by UCHL5 in HCV-Infected Cells

Ramachandran, Akshaya; Kumar, Binod; Waris, Gulam; Everly, David N.

doi:10.1128/spectrum.00755-21

Cited by 24 publications

(27 citation statements)

References 38 publications

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“…Previous studies have highlighted that the ubiquitin/deubiquitination post-translation modification of NLRP3 plays a critical role in regulating the NLRP3 activation. , As a key component of the ubiquitin–proteasome system, the 26S proteasome is responsible for the degradation of various polyubiquitinated proteins in cells, and its inhibition is likely to keep proteins in the polyubiquitination state without being degraded . On the basis of these analyses, we hypothesized that 27 might regulate the ubiquitin-proteasome system to block NLRP3 inflammasome activation via the inhibition of the 26S proteasome.…”

Section: Resultsmentioning

confidence: 99%

Discovery of a Novel Oral Proteasome Inhibitor to Block NLRP3 Inflammasome Activation with Anti-inflammation Activity

Sun

Chen

et al. 2022

J. Med. Chem.

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NLRP3 inflammasome activation plays a critical role in inflammation-related disorders. More small-molecule entities are needed to study the mechanism of NLRP3 inflammasome activation and to validate the efficacy and safety of the NLRP3 pathway. Herein, we report the discovery of an orally bioavailable proteasome inhibitor NIC-0102 (27) that specifically prevents NLRP3 inflammasome activation but has no effect on NLRC4 or AIM2 inflammasomes. In vitro studies revealed that NIC-0102 induced the polyubiquitination of NLRP3, interfered with the NLRP3–ASC interaction, and blocked ASC oligomerization, thereby resulting in the inhibition of NLRP3 inflammasome activation. In addition, NIC-0102 also inhibited the production of pro-IL-1β. Importantly, NIC-0102 showed potent anti-inflammatory effects on DSS-induced ulcerative colitis model in vivo. As a result of these studies, a potential small molecule is identified to demonstrate the possible link between the proteasome and NLRP3 pathway, which supports further exploration of potentially druggable nodes to modulate NLRP3 inflammasome activation.

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Section: Resultsmentioning

confidence: 99%

Discovery of a Novel Oral Proteasome Inhibitor to Block NLRP3 Inflammasome Activation with Anti-inflammation Activity

Sun

Chen

et al. 2022

J. Med. Chem.

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“…Uchl5, a deubiquitin enzyme involved in post-translational protein modification, plays a role in oxygen-dependent proline hydroxylation of HIF-α, IL-1 signaling, and neutrophil degranulation ( 47 ). A recent study has demonstrated that Uchl5 can deubiquitinate and activate NLRP3 in HCV-infected cells, leading to IL-1β maturation and secretion ( 48 ). However, its role in NLRP3 caused by cardiac I/R has not been reported.…”

Section: Discussionmentioning

confidence: 99%

Proteomics Revealed That Mitochondrial Function Contributed to the Protective Effect of Herba Siegesbeckiae Against Cardiac Ischemia/Reperfusion Injury

Wei

Pan

et al. 2022

Front. Cardiovasc. Med.

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BackgroundMyocardial ischemia/reperfusion (I/R) injury is the main obstacle to percutaneous coronary intervention, lacking effective therapeutic measures in a clinical setting. Herba Siegesbeckiae (HS) is a traditional herb with multiple pharmacological activities and evidence of cardiovascular protection. However, few data are available regarding the role of HS in cardiac I/R. This study aimed to explore the effect and underlying mechanism of HS aqueous extract on cardiac I/R injury.Materials and MethodsHerba Siegesbeckiae aqueous extract was prepared and analyzed by UHPLC-MS/MS. After intragastric administration of HS once daily for 7 days, male Sprague-Dawley rats were subjected to 30 min occlusion of the left anterior descending coronary artery followed by 120 min reperfusion to elicit I/R. Various parameters like myocardial infarction and apoptosis, 12-lead ECG and hemodynamics, cardiac morphology and myocardial enzymes, quantitative proteomics, mitochondrial ultrastructure and electron transport chain (ETC) function, oxidative stress and antioxidation, and NLRP3 inflammasome and inflammation were evaluated.ResultsThe chemical constituents of HS aqueous extract were mainly divided into flavonoids, diterpenoids, and organic acids. In vivo, HS aqueous extract notably alleviated myocardial I/R injury, as evidenced by a reduction in infarct size, apoptotic cells, and cardiac lesion enzymes; decline of ST-segment elevation; improvement of cardiac function; and preservation of morphology. Quantitative proteomics demonstrated that HS reversed the alteration in the expression of Adgb, Cbr1, Decr1, Eif5, Uchl5, Lmo7, Bdh1, Ckmt2, COX7A, and RT1-CE1 after I/R. In addition, HS preserved myocardial ultrastructure and restored the function of mitochondrial ETC complexes following exposure to I/R; HS significantly suppressed I/R-elicited increase of ROS, RNS, MDA, and 8-OHdG, restrained the acetylation of MnSOD, and recovered the activity of MnSOD; and HS reversed I/R-induced elevation of NLRP3 inflammasome and inhibited the release of inflammatory factors and pyroptosis.ConclusionHerba Siegesbeckiae aqueous extract ameliorated cardiac I/R injury, which is associated with mitigating oxidative stress, suppressing NLRP3 inflammasome, and restoring mitochondrial function by regulating the expression of Adgb, Cbr1, Decr1, Eif5, Uchl5, Lmo7, Bdh1, Ckmt2, COX7A, and RT1-CE1.

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“…UAF1/USP1 complex activates NLRP3 after deubiquitylation through Lys48 poly-ubiquitin chains and thus increases the level of NLRP3 intracellular levels by protecting it from degradation ( Song et al, 2020 ). UCHL5 deubiquitylation activity has been linked to NLRP3 inflammasome activation in the context of Chronic hepatitis C virus (HCV) infection but the ubiquitin chain types or ubiquitylation sites are unknown ( Ramachandran et al, 2021 ). ABRO1, a subunit of BRISC deubiquitylase complex, binds to NLRP3 in a phosphorylation-dependent manner through Ser194 to mediates the cleavage of Lys63 poly-ubiquitylation of NLRP3 leading to its activation ( Ren et al, 2019 ).…”

Section: Ubiquitylation Of Inflammasome Componentsmentioning

confidence: 99%

Posttranslational Regulation of Inflammasomes, Its Potential as Biomarkers and in the Identification of Novel Drugs Targets

Nanda

Vollmer²,

Pérez-Oliva

2022

Front. Cell Dev. Biol.

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In this review, we have summarized classical post-translational modifications (PTMs) such as phosphorylation, ubiquitylation, and SUMOylation of the different components of one of the most studied NLRP3, and other emerging inflammasomes. We will highlight how the discovery of these modifications have provided mechanistic insight into the biology, function, and regulation of these multiprotein complexes not only in the context of the innate immune system but also in adaptive immunity, hematopoiesis, bone marrow transplantation, as well and their role in human diseases. We have also collected available information concerning less-studied modifications such as acetylation, ADP-ribosylation, nitrosylation, prenylation, citrullination, and emphasized their relevance in the regulation of inflammasome complex formation. We have described disease-associated mutations affecting PTMs of inflammasome components. Finally, we have discussed how a deeper understanding of different PTMs can help the development of biomarkers and identification of novel drug targets to treat diseases caused by the malfunctioning of inflammasomes.

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Deubiquitination and Activation of the NLRP3 Inflammasome by UCHL5 in HCV-Infected Cells

Abstract: HCV infection induces inflammation leading to fibrosis, cirrhosis, and cancer. The current study identifies the mechanisms leading to the activation of the NLRP3 inflammasome in hepatocytes, which is an important site of viral replication.

Cited by 24 publications

References 38 publications

Discovery of a Novel Oral Proteasome Inhibitor to Block NLRP3 Inflammasome Activation with Anti-inflammation Activity

Discovery of a Novel Oral Proteasome Inhibitor to Block NLRP3 Inflammasome Activation with Anti-inflammation Activity

Proteomics Revealed That Mitochondrial Function Contributed to the Protective Effect of Herba Siegesbeckiae Against Cardiac Ischemia/Reperfusion Injury

Posttranslational Regulation of Inflammasomes, Its Potential as Biomarkers and in the Identification of Novel Drugs Targets

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