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The E3 ubiquitin ligase RNF115 regulates phagosome maturation and host response to bacterial infection

ABSTRACT: Phagocytosis is a key process in innate immunity and homeostasis. After particle uptake, newly formed phagosomes mature by acquisition of endo-lysosomal enzymes. Macrophage activation by interferon gamma (IFN-γ) increases microbicidal activity, but delays phagosomal maturation by an unknown mechanism. Using quantitative proteomics, we show that phagosomal proteins harbour high levels of typical and atypical ubiquitin chain types. Moreover, phagosomal ubiquitylation of vesicle trafficking proteins is substantially enhanced upon IFN-γ activation of macrophages, suggesting a role in regulating phagosomal functions. We identified the E3 ubiquitin ligase RNF115, which is enriched on phagosomes of IFN-γ activated macrophages, as an important regulator of phagosomal maturation. Loss of RNF115 protein or ligase activity enhanced phagosomal maturation and increased cytokine responses to bacterial infection, suggesting that both innate immune signalling from the phagosome and phagolysosomal trafficking are controlled through ubiquitylation. RNF115 knock-out mice show less tissue damage in response to S. aureus infection, indicating a role of RNF115 in inflammatory responses in vivo. In conclusion, RNF115 and phagosomal ubiquitylation are important regulators of innate immune functions during bacterial infections.

SUBMITTER: Dr. Orsolya Bilkei-Gorzo

PROVIDER: S-SCDT-10_15252-EMBJ_2021108970 | biostudies-other |

REPOSITORIES: biostudies-other

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The E3 ubiquitin ligase RNF115 regulates phagosome maturation and host response to bacterial infection.

Project description:Phagocytosis is a key process in innate immunity and homeostasis. After particle uptake, newly formed phagosomes mature by acquisition of endolysosomal enzymes. Macrophage activation by interferon gamma (IFN-γ) increases microbicidal activity, but delays phagosomal maturation by an unknown mechanism. Using quantitative proteomics, we show that phagosomal proteins harbour high levels of typical and atypical ubiquitin chain types. Moreover, phagosomal ubiquitylation of vesicle trafficking proteins is substantially enhanced upon IFN-γ activation of macrophages, suggesting a role in regulating phagosomal functions. We identified the E3 ubiquitin ligase RNF115, which is enriched on phagosomes of IFN-γ activated macrophages, as an important regulator of phagosomal maturation. Loss of RNF115 protein or ligase activity enhanced phagosomal maturation and increased cytokine responses to bacterial infection, suggesting that both innate immune signalling from the phagosome and phagolysosomal trafficking are controlled through ubiquitylation. RNF115 knock-out mice show less tissue damage in response to S. aureus infection, indicating a role of RNF115 in inflammatory responses in vivo. In conclusion, RNF115 and phagosomal ubiquitylation are important regulators of innate immune functions during bacterial infections.

| S-EPMC9713710 | biostudies-literature

The E3 ubiquitin ligase RNF115 regulates phagosome maturation and host response to infection

Project description:Phagocytosis is an essential process for the microbicidal function of professional phagocytes, in which phagosome maturation plays a critical role. Macrophage activation by interferons (IFN) increases their microbicidal activity, but delays phagosomal maturation. Here, we investigated the role of ubiquitylation in phagosome functions. We show that phagosomal proteins are ubiquitylated and that phagosomes contain diverse ubiquitin chain types, including atypical ubiquitin chains. IFN-γ activation of macrophages substantially enhanced phagosomal ubiquitylation of both innate immune response proteins and vesicle trafficking proteins. We identified the E3 ubiquitin ligase RNF115, which is enriched on phagosomes of IFN-γ activated macrophages, as an important regulator of phagosomal maturation. Loss of RNF115 protein or ubiquitin ligase activity facilitated enhanced phagosomal maturation, and increased cytokine responses to Staphylococcus aureus. Our data suggests that both innate immune signalling and phagolysosomal trafficking are controlled through ubiquitylation. In conclusion, we identify RNF115 and ubiquitylation as important regulators of innate immune signalling from the phagosome during bacterial infections.

2022-07-20 | PXD026843 | Pride

Interplay between bacterial deubiquitinase and ubiquitin E3 ligase regulates ubiquitin dynamics on Legionella phagosomes.

Project description:Legionella pneumophila extensively modulates the host ubiquitin network to create the Legionella-containing vacuole (LCV) for its replication. Many of its virulence factors function as ubiquitin ligases or deubiquitinases (DUBs). Here, we identify Lem27 as a DUB that displays a preference for diubiquitin formed by K6, K11, or K48. Lem27 is associated with the LCV where it regulates Rab10 ubiquitination in concert with SidC and SdcA, two bacterial E3 ubiquitin ligases. Structural analysis of the complex formed by an active fragment of Lem27 and the substrate-based suicide inhibitor ubiquitin-propargylamide (PA) reveals that it harbors a fold resembling those in the OTU1 DUB subfamily with a Cys-His catalytic dyad and that it recognizes ubiquitin via extensive hydrogen bonding at six contact sites. Our results establish Lem27 as a DUB that functions to regulate protein ubiquitination on L. pneumophila phagosomes by counteracting the activity of bacterial ubiquitin E3 ligases.

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A bacterial E3 ubiquitin ligase IpaH9.8 targets NEMO/IKKgamma to dampen the host NF-kappaB-mediated inflammatory response.

Project description:NF-kappaB (nuclear factor kappaB) has a pivotal role in many cellular processes, including the inflammatory and immune responses and, therefore, its activation is tightly regulated by the IKK (IkappaB kinase) complex and by IkappaBalpha degradation. When Shigella bacteria multiply within epithelial cells they release peptidoglycans, which are recognized by Nod1 and stimulate the NF-kappaB pathway, thus leading to a severe inflammatory response. Here, we show that IpaH9.8, a Shigella effector possessing E3 ligase activity, dampens the NF-kappaB-mediated inflammatory response to the bacterial infection in a unique way. IpaH9.8 interacts with NEMO/IKKgamma and ABIN-1, a ubiquitin-binding adaptor protein, promoting ABIN-1-dependent polyubiquitylation of NEMO. Consequently, polyubiquitylated NEMO undergoes proteasome-dependent degradation, which perturbs NF-kappaB activation. As NEMO is essential for NF-kappaB activation, we propose that the polyubiquitylation and degradation of NEMO during Shigella infection is a new bacterial strategy to modulate host inflammatory responses.

| S-EPMC3107189 | biostudies-literature

Ubiquitin E3 ligase FIEL1 regulates fibrotic lung injury through SUMO-E3 ligase PIAS4.

Project description:The E3 small ubiquitin-like modifier (SUMO) protein ligase protein inhibitor of activated STAT 4 (PIAS4) is a pivotal protein in regulating the TGFβ pathway. In this study, we discovered a new protein isoform encoded by KIAA0317, termed fibrosis-inducing E3 ligase 1 (FIEL1), which potently stimulates the TGFβ signaling pathway through the site-specific ubiquitination of PIAS4. FIEL1 targets PIAS4 using a double locking mechanism that is facilitated by the kinases PKCζ and GSK3β. Specifically, PKCζ phosphorylation of PIAS4 and GSK3β phosphorylation of FIEL1 are both essential for the degradation of PIAS4. FIEL1 protein is highly expressed in lung tissues from patients with idiopathic pulmonary fibrosis (IPF), whereas PIAS4 protein levels are significantly reduced. FIEL1 overexpression significantly increases fibrosis in a bleomycin murine model, whereas FIEL1 knockdown attenuates fibrotic conditions. Further, we developed a first-in-class small molecule inhibitor toward FIEL1 that is highly effective in ameliorating fibrosis in mice. This study provides a basis for IPF therapeutic intervention by modulating PIAS4 protein abundance.

| S-EPMC4886359 | biostudies-literature

A bacterial E3 ubiquitin ligase targets a host protein kinase to disrupt plant immunity.

Project description:Many bacterial pathogens of plants and animals use a type III secretion system to deliver diverse virulence-associated 'effector' proteins into the host cell. The mechanisms by which these effectors act are mostly unknown; however, they often promote disease by suppressing host immunity. One type III effector, AvrPtoB, expressed by the plant pathogen Pseudomonas syringae pv. tomato, has a carboxy-terminal domain that is an E3 ubiquitin ligase. Deletion of this domain allows an amino-terminal region of AvrPtoB (AvrPtoB(1-387)) to be detected by certain tomato varieties leading to immunity-associated programmed cell death. Here we show that a host kinase, Fen, physically interacts with AvrPtoB(1-387 )and is responsible for activating the plant immune response. The AvrPtoB E3 ligase specifically ubiquitinates Fen and promotes its degradation in a proteasome-dependent manner. This degradation leads to disease susceptibility in Fen-expressing tomato lines. Various wild species of tomato were found to exhibit immunity in response to AvrPtoB(1-387 )and not to full-length AvrPtoB. Thus, by acquiring an E3 ligase domain, AvrPtoB has thwarted a highly conserved host resistance mechanism.

| S-EPMC2265072 | biostudies-literature

The SCFFBXO3 ubiquitin E3 ligase regulates inflammation in atherosclerosis.

Project description:Inflammation is critical in the pathobiology of atherosclerosis. An essential player in the inflammatory process in atherosclerosis are macrophages that scavenge oxidatively modified low-density lipoproteins (OxLDL) deposited in the subendothelium of systemic arteries that secrete a myriad of pro-inflammatory mediators. Here, we identified that a subunit of the Skp-Cullin-F-box ubiquitin E3 ligase apparatus, termed FBXO3, modulates the inflammatory response in atherosclerosis. Specifically, individuals with a hypofunctioning genetic variant of FBXO3 develop less atherosclerosis. FBXO3 protein is present in cells of monocytic lineage within carotid plaques and its levels increase in those with symptomatic compared with asymptomatic atherosclerosis. Further, cellular depletion or small molecule inhibition of FBXO3 significantly reduced the inflammatory response to OxLDL by macrophages without altering OxLDL uptake. Thus, FBXO3 potentiates vascular inflammation and atherosclerosis that can be effectively mitigated by a small molecule inhibitor.

| S-EPMC7425077 | biostudies-literature

E3 ubiquitin ligase SP1 regulates peroxisome biogenesis in Arabidopsis.

Project description:Peroxisomes are ubiquitous eukaryotic organelles that play pivotal roles in a suite of metabolic processes and often act coordinately with other organelles, such as chloroplasts and mitochondria. Peroxisomes import proteins to the peroxisome matrix by peroxins (PEX proteins), but how the function of the PEX proteins is regulated is poorly understood. In this study, we identified the Arabidopsis RING (really interesting new gene) type E3 ubiquitin ligase SP1 [suppressor of plastid protein import locus 1 (ppi1) 1] as a peroxisome membrane protein with a regulatory role in peroxisome protein import. SP1 interacts physically with the two components of the peroxisome protein docking complex PEX13-PEX14 and the (RING)-finger peroxin PEX2. Loss of SP1 function suppresses defects of the pex14-2 and pex13-1 mutants, and SP1 is involved in the degradation of PEX13 and possibly PEX14 and all three RING peroxins. An in vivo ubiquitination assay showed that SP1 has the ability to promote PEX13 ubiquitination. Our study has revealed that, in addition to its previously reported function in chloroplast biogenesis, SP1 plays a role in peroxisome biogenesis. The same E3 ubiquitin ligase promotes the destabilization of components of two distinct protein-import machineries, indicating that degradation of organelle biogenesis factors by the ubiquitin-proteasome system may constitute an important regulatory mechanism in coordinating the biogenesis of metabolically linked organelles in eukaryotes.

| S-EPMC5135305 | biostudies-literature

The E3 Ubiquitin Ligase RNF7 Negatively Regulates CARD14/CARMA2sh Signaling.

Project description:The three CARD-containing MAGUK (CARMA) proteins function as scaffolding molecules that regulate activation of the pro-inflammatory transcription factor NF-?B. Recently, mutations in CARMA2 have been linked to psoriasis susceptibility due to their acquired altered capacity to activate NF-?B. By means of two-hybrid screening with yeast, we identified RING finger protein 7 (RNF7) as an interactor of CARMA2. We present evidence that RNF7 functions as a negative regulator of the NF-?B-activating capacity of CARMA2. Mechanistically, RNF7 influences CARMA2 signaling by regulating the ubiquitination state of MALT1 and the NF-?B-regulatory molecule NEMO. Interestingly, CARMA2short (CARMA2sh) mutants associated with psoriasis susceptibility escape the negative control exerted by RNF7. In conclusion, our findings identify a new mechanism through which the ability of CARMA2 to activate NF-?B is regulated, which could have significant implications for our understanding of why mutations of this protein trigger human psoriasis.

| S-EPMC5751184 | biostudies-other

The Arabidopsis E3 ubiquitin ligase PUB4 regulates BIK1 and is targeted by a bacterial type-III effector

Project description:Plant immunity is tightly controlled by a complex and dynamic regulatory network, which ensures optimal activation upon detection of potential pathogens. Accordingly, each component of this network is a potential target for manipulation by pathogens. Here, we report that RipAC, a type III-secreted effector from the bacterial pathogen Ralstonia solanacearum, targets the plant E3 ubiquitin ligase PUB4 to inhibit pattern-triggered immunity (PTI). PUB4 plays a positive role in PTI by regulating the homeostasis of the central immune kinase BIK1. Before PAMP perception, PUB4 promotes the degradation of non-activated BIK1, while, after PAMP perception, PUB4 contributes to the accumulation of activated BIK1. RipAC leads to BIK1 degradation, which correlates with its PTI-inhibitory activity. RipAC causes a reduction in pathogen-associated molecular pattern (PAMP)-induced PUB4 accumulation and phosphorylation. Our results shed light on the role played by PUB4 in immune regulation, and illustrate an indirect targeting of the immune signalling hub BIK1 by a bacterial effector.

| S-SCDT-10_15252-EMBJ_2020107257 | biostudies-other

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