Degradation of the Deubiquitinating Enzyme USP33 Is Mediated by p97 and the Ubiquitin Ligase HERC2

Chan, Nickie C.; Besten, Willem den; Sweredoski, Michael J.; Hess, Sonja; Deshaies, Raymond J.; Chan, David C.

doi:10.1074/jbc.m114.569392

Cited by 31 publications

(24 citation statements)

References 53 publications

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“…The ubiquitin-specific processing protease 33 (USP33), as a deubiquitinating enzyme, controls the ubiquitylation of RalB GTPase at Lys 47 [8,29]. Consistent with the data of RalB, the expression level of USP33 was decreased by DHA or rapamycin treatment, while not change with 3-MA ( Fig.…”

Section: Connecting the Inflammasome And Autophagy Pathwayssupporting

confidence: 83%

RalB degradation by dihydroartemisinin induces autophagy and IFI16/caspase-1 inflammasome depression in the human Laryngeal squamous cell carcinoma

Shi

Wang

et al. 2020

Preprint

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Background Interferon-inducible 16 (IFI16) /caspase-1 inflammasome activates and secretes IL-1β. However, whether the IFI16 inflammasome involved in human Laryngeal squamous cell carcinoma is still unclear. Autophagy directly removed inflammasome components and limited early IL-1β production. RalB is required for the crosstalk between inflammasome and autophagy in macrophages. Dihydroartemisinin (DHA), the main derived ingredient of artemisinin, has a variety of biological activities. The mechanism of DHA in regulation the crosstalk between IFI16 inflammasome and autophagy by inhibiting RalB expression was analyzed in order to provide clues for new therapeutic methods in laryngeal cancer. Methods The expression of IFI16 was analyzed by Oncomine and GEPIA databases and detected by Western blot and immunohistochemistry. The relationship between IFI16 inflammasome and autophagy was investigated by transmission electron microscopy, immunofluorescence assay, etc. in Hep-2, Cal-27 and HeLa cells with DHA treatment. Hep-2 cell xenograft tumor in nude mice were used to assess the effect of DHA on laryngeal cancer. Results The study was firstly reported that IFI16 was overexpressed and positively correlated with caspase-1 in laryngeal carcinoma tissues. DHA alone or in combination with cisplatin significantly inhibited inflammasome activation and reduced IL-1β production in the xenograft tumor microenvironment of Hep-2 cell xenograft tumor in nude mice. Mechanistically, we found that DHA degraded RalB by inhibiting USP33 expression, leading to triggered autophagy. Meanwhile, enhanced autophagy can reduce the expression of RalB and USP33. Therefore, DHA depresses RalB, resulting in formation a positive feedback loop between USP33 and autophagy. Further, DHA promotes autophagy, which suppresses the IFI16/caspase-1 inflammasome activation and IL-1β production. Conclusions Therefore, our findings demonstrate that DHA may act as a RalB inhibitor to regulate the crosstalk between autophagy and IFI16/caspase-1 inflammasome, which inhibits IL-1β production in tumor microenvironment.

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Section: Connecting the Inflammasome And Autophagy Pathwayssupporting

confidence: 83%

RalB degradation by dihydroartemisinin induces autophagy and IFI16/caspase-1 inflammasome depression in the human Laryngeal squamous cell carcinoma

Shi

Wang

et al. 2020

Preprint

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“… 13 HERC2 also interacts with the deubiquitinating enzyme USP33 and the SCF protein FBXL5, regulating their stability through ubiquitin-mediated proteasomal degradation. 14 , 15 HERC2 has also been shown to regulate centrosome morphology and ubiquitin ligase activity through interactions with NEURL4 and UBE3A (also known as E6AP), respectively. NEURL4 and HERC2 were identified as interactors of the centrosomal protein CP110, and their binding is required for maintenance of centrosome integrity.…”

Section: Introductionmentioning

confidence: 99%

Proteomic Analysis and Identification of Cellular Interactors of the Giant Ubiquitin Ligase HERC2

et al. 2014

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HERC2 is a large E3 ubiquitin ligase with multiple structural domains that has been implicated in an array of cellular processes. Mutations in HERC2 are linked to developmental delays and impairment caused by nervous system dysfunction, such as Angelman Syndrome and autism-spectrum disorders. However, HERC2 cellular activity and regulation remain poorly understood. We used a broad proteomic approach to survey the landscape of cellular proteins that interact with HERC2. We identified nearly 300 potential interactors, a subset of which we validated binding to HERC2. The potential HERC2 interactors included the eukaryotic translation initiation factor 3 complex, the intracellular transport COPI coatomer complex, the glycogen regulator phosphorylase kinase, beta-catenin, PI3 kinase, and proteins involved in fatty acid transport and iron homeostasis. Through a complex bioinformatic analysis of potential interactors, we linked HERC2 to cellular processes including intracellular protein trafficking and transport, metabolism of cellular energy, and protein translation. Given its size, multidomain structure, and association with various cellular activities, HERC2 may function as a scaffold to integrate protein complexes and bridge critical cellular pathways. This work provides a significant resource with which to interrogate HERC2 function more deeply and evaluate its contributions to mechanisms governing cellular homeostasis and disease.

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“…HERC2 has been shown to regulate the stability of several proteins involved in DNA damage repair. Additionally, it targets the deubiquitinating enzyme USP33, involved in cancer cell migration, and β2-adrenergic receptor signalling (Chan et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

A new HECT ubiquitin ligase regulating chemotaxis and development in Dictyostelium discoideum

Pergolizzi

Bracco

Bozzaro

2017

Journal of Cell Science

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Cyclic AMP (cAMP) binding to G-protein-coupled receptors (GPCRs) orchestrates chemotaxis and development in Dictyostelium. By activating the RasC-TORC2-PKB (PKB is also known as AKT in mammals) module, cAMP regulates cell polarization during chemotaxis. TORC2 also mediates GPCR-dependent stimulation of adenylyl cyclase A (ACA), enhancing cAMP relay and developmental gene expression. Thus, mutants defective in the TORC2 Pia subunit (also known as Rictor in mammals) are impaired in chemotaxis and development. Near-saturation mutagenesis of a Pia mutant by random gene disruption led to selection of two suppressor mutants in which spontaneous chemotaxis and development were restored. PKB phosphorylation and chemotactic cell polarization were rescued, whereas Pia-dependent ACA stimulation was not restored but bypassed, leading to cAMP-dependent developmental gene expression. Knocking out the gene encoding the adenylylcyclase B (ACB) in the parental strain showed ACB to be essential for this process. The gene tagged in the suppressor mutants encodes a newly unidentified HECT ubiquitin ligase that is homologous to mammalian HERC1, but harbours a pleckstrin homology domain. Expression of the isolated wild-type HECT domain, but not a mutant HECT C5185S form, from this protein was sufficient to reconstitute the parental phenotype. The new ubiquitin ligase appears to regulate cell sensitivity to cAMP signalling and TORC2-dependent PKB phosphorylation.

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Degradation of the Deubiquitinating Enzyme USP33 Is Mediated by p97 and the Ubiquitin Ligase HERC2

Cited by 31 publications

References 53 publications

RalB degradation by dihydroartemisinin induces autophagy and IFI16/caspase-1 inflammasome depression in the human Laryngeal squamous cell carcinoma

RalB degradation by dihydroartemisinin induces autophagy and IFI16/caspase-1 inflammasome depression in the human Laryngeal squamous cell carcinoma

Proteomic Analysis and Identification of Cellular Interactors of the Giant Ubiquitin Ligase HERC2

A new HECT ubiquitin ligase regulating chemotaxis and development in Dictyostelium discoideum

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