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SIAH ubiquitin E3 ligases as modulators of inflammatory gene expression.

ABSTRACT: The functionally redundant ubiquitin E3 ligases SIAH1 and SIAH2 have been implicated in the regulation of metabolism and the hypoxic response, while their role in other signal-mediated processes such inflammatory gene expression remains to be defined. Here we have downregulated the expression of both SIAH proteins with specific siRNAs and investigated the functional consequences for IL-1α-induced gene expression. The knockdown of SIAH1/2 modulated the expression of approximately one third of IL-1α-regulated genes. These effects were not due to changes in the NF-κB and MAPK signaling pathways and rather employed further processes including those mediated by the coactivator p300. Most of the proteins encoded by SIAH1/2-regulated genes form a regulatory network of proinflammatory factors. Thus SIAH1/2 proteins function as variable rheostats that control the amplitude rather than the principal activation of the inflammatory gene response.

SUBMITTER: Schmitz ML

PROVIDER: S-EPMC8904615 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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SIAH ubiquitin E3 ligases as modulators of inflammatory gene expression.

Schmitz M Lienhard ML Dreute Jan J Pfisterer Maximilian M Günther Stefan S Kracht Michael M Chillappagari Shashipavan S

Heliyon 20220301 3

The functionally redundant ubiquitin E3 ligases SIAH1 and SIAH2 have been implicated in the regulation of metabolism and the hypoxic response, while their role in other signal-mediated processes such inflammatory gene expression remains to be defined. Here we have downregulated the expression of both SIAH proteins with specific siRNAs and investigated the functional consequences for IL-1α-induced gene expression. The knockdown of SIAH1/2 modulated the expression of approximately one third of IL- ...[more]

PMID: 35284677

Similar Datasets

SIAH ubiquitin E3 ligases as modulators of inflammatory gene expression

Project description:The functionally redundant ubiquitin E3 ligases SIAH1 and SIAH2 have been implicated in the regulation of several processes, but their role in inflammatory signaling and gene expression remains unclear. Here we have downregulated the expression of both SIAH proteins with specific siRNAs and investigated the functional consequences for IL-1α-induced gene expression and the signaling pathways activating NF-κB and AP1. The knockdown of SIAH1/2 had no significant impact on IL-1α-induced activation of NF-κB and MAPK signaling pathways, but modulated the expression of approximately one third of IL-1α-regulated genes. Most of the proteins encoded by SIAH1/2-regulated genes form a regulatory network of proinflammatory factors. Thus SIAH1/2 proteins function as variable rheostats that control the amplitude of inflammatory gene expression.

2022-02-01 | GSE179190 | GEO

SIAH ubiquitin E3 ligases as modulators of inflammatory gene expression

Project description:SIAH ubiquitin E3 ligases as modulators of inflammatory gene expression

| PRJNA742677 | ENA

The SIAH E3 ubiquitin ligases promote Wnt/β-catenin signaling through mediating Wnt-induced Axin degradation.

Project description:The Wnt/β-catenin signaling pathway plays essential roles in embryonic development and adult tissue homeostasis. Axin is a concentration-limiting factor responsible for the formation of the β-catenin destruction complex. Wnt signaling itself promotes the degradation of Axin. However, the underlying molecular mechanism and biological relevance of this targeting of Axin have not been elucidated. Here, we identify SIAH1/2 (SIAH) as the E3 ligase mediating Wnt-induced Axin degradation. SIAH proteins promote the ubiquitination and proteasomal degradation of Axin through interacting with a VxP motif in the GSK3-binding domain of Axin, and this function of SIAH is counteracted by GSK3 binding to Axin. Structural analysis reveals that the Axin segment responsible for SIAH binding is also involved in GSK3 binding but adopts distinct conformations in Axin/SIAH and Axin/GSK3 complexes. Knockout of SIAH1 blocks Wnt-induced Axin ubiquitination and attenuates Wnt-induced β-catenin stabilization. Our data suggest that Wnt-induced dissociation of the Axin/GSK3 complex allows SIAH to interact with Axin not associated with GSK3 and promote its degradation and that SIAH-mediated Axin degradation represents an important feed-forward mechanism to achieve sustained Wnt/β-catenin signaling.

| S-EPMC5458757 | biostudies-literature

Rice SIAH E3 Ligases Interact with RMD Formin and Affect Plant Morphology.

Project description:Formins are actin-binding proteins that are key to maintaining the actin cytoskeleton in cells. However, molecular mechanisms controlling the stability of formin proteins in plants remain unknown. Here, we have identified six rice SIAH-type E3 ligases, named RIP1-6 (RMD Interacting Protein 1-6) respectively, with ubiquitination enzyme activity in vitro. All six proteins can form homo- and hetero-dimers with themselves, and hetero-dimers with type II formin RMD/OsFH5. In vivo assays showed that RIP1-6 proteins localize in the cytoplasm with a punctate distribution, and all of them interact with RMD to change its native diffuse cytoplasmic localization to match that of RIP1-6. To our surprise, degradation experiments revealed that RIP1, RIP5, and RIP6 decrease rather than increase the degradation rate of RMD. Genetic analyses revealed redundancy between these six genes; either single or double mutants did not show any obvious phenotypes. However, the sextuple rip1-6 mutant displayed dwarf height, wrinkled seeds and wider leaves that were similar to the previously reported rmd mutant, and defective microfilaments and increased flag leaf angles that were not reported in rmd mutant. Collectively, our study provides insights into the mechanisms determining formin protein stability in plants.

| S-EPMC8786996 | biostudies-literature

Role of RING-Type E3 Ubiquitin Ligases in Inflammatory Signalling and Inflammatory Bowel Disease.

Project description:Ubiquitination is a three-step enzymatic cascade for posttranslational protein modification. It includes the ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligase (E3). RING-type E3 ubiquitin ligases catalyse the posttranslational proteolytic and nonproteolytic functions in various physiological and pathological processes, such as inflammation-associated signal transduction. Resulting from the diversity of substrates and functional mechanisms, RING-type ligases regulate microbe recognition and inflammation by being involved in multiple inflammatory signalling pathways. These processes also occur in autoimmune diseases, especially inflammatory bowel disease (IBD). To understand the importance of RING-type ligases in inflammation, we have discussed their functional mechanisms in multiple inflammation-associated pathways and correlation between RING-type ligases and IBD. Owing to the limited data on the biology of RING-type ligases, there is an urgent need to analyse their potential as biomarkers and therapeutic targets in IBD in the future.

| S-EPMC7436281 | biostudies-literature

Suramin inhibits cullin-RING E3 ubiquitin ligases.

Project description:Cullin-RING E3 ubiquitin ligases (CRL) control a myriad of biological processes by directing numerous protein substrates for proteasomal degradation. Key to CRL activity is the recruitment of the E2 ubiquitin-conjugating enzyme Cdc34 through electrostatic interactions between E3's cullin conserved basic canyon and the acidic C terminus of the E2 enzyme. This report demonstrates that a small-molecule compound, suramin, can inhibit CRL activity by disrupting its ability to recruit Cdc34. Suramin, an antitrypansomal drug that also possesses antitumor activity, was identified here through a fluorescence-based high-throughput screen as an inhibitor of ubiquitination. Suramin was shown to target cullin 1's conserved basic canyon and to block its binding to Cdc34. Suramin inhibits the activity of a variety of CRL complexes containing cullin 2, 3, and 4A. When introduced into cells, suramin induced accumulation of CRL substrates. These observations help develop a strategy of regulating ubiquitination by targeting an E2-E3 interface through small-molecule modulators.

| S-EPMC4833235 | biostudies-literature

End-Binding E3 Ubiquitin Ligases Enable Protease Signaling.

Project description:Post-translational modifications (PTMs) direct the assembly of protein complexes. In this context, proteolysis is a unique PTM because it is irreversible; the hydrolysis of the peptide backbone generates separate fragments bearing a new N and C terminus. Proteolysis can "re-wire" protein-protein interactions (PPIs) via the recruitment of end-binding proteins to new termini. In this review, we focus on the role of proteolysis in specifically creating complexes by recruiting E3 ubiquitin ligases to new N and C termini. These complexes potentiate proteolytic signaling by "erasing" proteolytic modifications. This activity tunes the duration and magnitude of protease signaling events. Recent work has shown that the stepwise process of proteolysis, end-binding by E3 ubiquitin ligases, and fragment turnover is associated with both the nascent N terminus (i.e., N-degron pathways) and the nascent C terminus (i.e., the C-degron pathways). Here, we discuss how these pathways might harmonize protease signaling with protein homeostasis (i.e., proteostasis).

| S-EPMC7400744 | biostudies-literature

Cullin-RING E3 Ubiquitin Ligases: Bridges to Destruction.

Project description:Ubiquitination is a highly conserved post-translational modification in eukaryotes, well known for targeting proteins for degradation by the 26S proteasome. Proteins destined for proteasomal degradation are selected by E3 ubiquitin ligases. Cullin-RING E3 ubiquitin ligases (CRLs) are the largest superfamily of E3 ubiquitin ligases, with over 400 members known in mammals. These modular complexes are tightly regulated in the cell. In this chapter, we highlight recent structural and biochemical advances shedding light on the assembly and architecture of cullin-RING ligases, their dynamic regulation by a variety of host factors, and their manipulation by viral pathogens and small molecules.

| S-EPMC7205596 | biostudies-literature

BioE3 identifies specific substrates of ubiquitin E3 ligases.

Project description:Hundreds of E3 ligases play a critical role in recognizing specific substrates for modification by ubiquitin (Ub). Separating genuine targets of E3s from E3-interactors remains a challenge. We present BioE3, a powerful approach for matching substrates to Ub E3 ligases of interest. Using BirA-E3 ligase fusions and bioUb, site-specific biotinylation of Ub-modified substrates of particular E3s facilitates proteomic identification. We show that BioE3 identifies both known and new targets of two RING-type E3 ligases: RNF4 (DNA damage response, PML bodies), and MIB1 (endocytosis, autophagy, centrosome dynamics). Versatile BioE3 identifies targets of an organelle-specific E3 (MARCH5) and a relatively uncharacterized E3 (RNF214). Furthermore, BioE3 works with NEDD4, a HECT-type E3, identifying new targets linked to vesicular trafficking. BioE3 detects altered specificity in response to chemicals, opening avenues for targeted protein degradation, and may be applicable for other Ub-likes (UbLs, e.g., SUMO) and E3 types. BioE3 applications shed light on cellular regulation by the complex UbL network.

| S-EPMC10667490 | biostudies-literature

The NEL Family of Bacterial E3 Ubiquitin Ligases.

Project description:Some pathogenic or symbiotic Gram-negative bacteria can manipulate the ubiquitination system of the eukaryotic host cell using a variety of strategies. Members of the genera Salmonella, Shigella, Sinorhizobium, and Ralstonia, among others, express E3 ubiquitin ligases that belong to the NEL family. These bacteria use type III secretion systems to translocate these proteins into host cells, where they will find their targets. In this review, we first introduce type III secretion systems and the ubiquitination process and consider the various ways bacteria use to alter the ubiquitin ligation machinery. We then focus on the members of the NEL family, their expression, translocation, and subcellular localization in the host cell, and we review what is known about the structure of these proteins, their function in virulence or symbiosis, and their specific targets.

| S-EPMC9320238 | biostudies-literature

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