SOCS-1 Mediates Ubiquitylation and Degradation of GM-CSF Receptor

Bunda, Severa; Kommaraju, Kamya; Heir, Pardeep; Ohh, Michael

doi:10.1371/journal.pone.0076370

Cited by 21 publications

(15 citation statements)

References 25 publications

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“…GM-CSF drives pathogenic inflammation in autoimmune disorders such as RA and MS, and its signaling therefore needs to be terminated after activation. Various SOCS family members have been suggested to be induced by and therefore control GM-CSF signaling ( Bunda et al, 2013 ; Esashi et al, 2008 ; Jackson et al, 2004 ). Here, we have provided physiological evidence that CIS is a bona fide inhibitor of GM-CSF signaling, in a classic negative feedback manner.…”

Section: Discussionmentioning

confidence: 99%

“…SOCS family proteins possess a central SH2 domain (which binds to phosphorylated tyrosine motifs in target proteins) and a C-terminal SOCS box that mediates the formation of an E3 ubiquitin ligase complex to ubiquitinate SOCS-interacting proteins for proteasomal degradation ( Morris et al, 2018 ). Although a number of SOCS family members have been proposed ( Bunda et al, 2013 ; Esashi et al, 2008 ; Jackson et al, 2004 ), whether GM-CSF signaling induces direct, stimulus-induced negative regulation has not been resolved ( Wicks and Roberts, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

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NK cell–derived GM-CSF potentiates inflammatory arthritis and is negatively regulated by CIS

Louis

Souza-Fonseca-Guimarães

Yang

et al. 2020

Journal of Experimental Medicine

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Despite increasing recognition of the importance of GM-CSF in autoimmune disease, it remains unclear how GM-CSF is regulated at sites of tissue inflammation. Using GM-CSF fate reporter mice, we show that synovial NK cells produce GM-CSF in autoantibody-mediated inflammatory arthritis. Synovial NK cells promote a neutrophilic inflammatory cell infiltrate, and persistent arthritis, via GM-CSF production, as deletion of NK cells, or specific ablation of GM-CSF production in NK cells, abrogated disease. Synovial NK cell production of GM-CSF is IL-18–dependent. Furthermore, we show that cytokine-inducible SH2-containing protein (CIS) is crucial in limiting GM-CSF signaling not only during inflammatory arthritis but also in experimental allergic encephalomyelitis (EAE), a murine model of multiple sclerosis. Thus, a cellular cascade of synovial macrophages, NK cells, and neutrophils mediates persistent joint inflammation via production of IL-18 and GM-CSF. Endogenous CIS provides a key brake on signaling through the GM-CSF receptor. These findings shed new light on GM-CSF biology in sterile tissue inflammation and identify several potential therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

NK cell–derived GM-CSF potentiates inflammatory arthritis and is negatively regulated by CIS

Louis

Souza-Fonseca-Guimarães

Yang

et al. 2020

Journal of Experimental Medicine

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“…SOCS1 inhibition of Jak is known to involve molecular interaction of SOCS1 with tyrosine phosphorylated Jak [ 33 , 35 ]. SOCS1 also has been reported to bind other phosphorylated substrates, leading to SOCS-box mediated degradation [ 36 , 37 ]. Hence, in order to find out whether the observed SOCS1 inhibition of Src involves interaction of the two molecules, co-immunoprecipitation assay was performed.…”

Section: Resultsmentioning

confidence: 99%

Mechanism of suppressors of cytokine signaling 1 inhibition of epithelial-mesenchymal transition signaling through ROS regulation in colon cancer cells: suppression of Src leading to thioredoxin up-regulation

2016

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Reactive oxygen species (ROS) participate in malignant progression of cancers including epithelial-mesenchymal transition (EMT). We have investigated the role of suppressors of cytokine signaling (SOCS)1 as an inhibitor of ROS-induced EMT using colon cancer cell lines transduced with SOCS1 and shSOCS1. Hydrogen peroxide treatment induced EMT features such as elevation of vimentin and Snail with a corresponding reduction of E-cadherin. The EMT markers are significantly decreased upon SOCS1 over-expression while increased under SOCS1 knock-down. SOCS1 inhibited ROS signaling pathways associated with EMT such as Src, Jak, and p65. Of note, strong up-regulation of Src activity in SOCS1-ablated cells was responsible for the elevated signaling leading to EMT, as shSrc or Src inhibitor abolished the shSOCS1-induced promotion of EMT response. Suppression of ROS-inducible EMT markers and invasion in SOCS1 over-expressing cells correlated with significantly low intracellular ROS levels in these cells. Analysis of antioxidant enzymes in SOCS1-transduced cells revealed a selective up-regulation of thioredoxin (Trx1), while thioredoxin ablation restored ROS levels and the associated EMT markers. As a mechanism of thioredoxin up-regulation by SOCS1, inhibition of Src activity promoting nuclear translocation of Nrf-2 is proposed. Taken together, our data strongly indicate that SOCS1 antagonizes EMT by suppressing Src activity, leading to thioredoxin expression and down-regulation of ROS levels in colon cancer cells.

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“…These two phenotypes are differentially expressed following inflammatory stimulus (M1) such LPS and/or IFN-alpha [31] or anti-inflammatory stimulus (M2) such as IL-10, IL-13, IL-14, and glucocorticoids [32]. Moreover, it is well known that macrophages express ubiquitin-proteasome system (UPS) and their activities are regulated by this system [33, 34]. Interestingly, we show that the intravitreal administration of resolvin D1 in LPS-rats also causes reduction of the ubiquitin-proteasome system expression within the eye.…”

Section: Discussionmentioning

confidence: 99%

Protection from Endotoxic Uveitis by Intravitreal Resolvin D1: Involvement of Lymphocytes, miRNAs, Ubiquitin‐Proteasome, and M1/M2 Macrophages

Rossi

Filippo

Gesualdo

et al. 2015

Mediators of Inflammation

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This study investigated the protective effects of intravitreal Resolvin D1 (RvD1) against LPS-induced rat endotoxic uveitis (EIU). RvD1 was administered into the right eye at a single injection of 5 μL volume containing 10–100–1000 ng/kg RvD1 1 h post-LPS injection (200 μg, Salmonella minnesota) into thefootpad of Sprague-Dawley rats. 24 h later, the eye was enucleated and examined for clinical, biochemical, and immunohistochemical evaluations. RvD1 significantly and dose-dependently decreased the clinical score attributed to EIU, starting from the dose of 10 ng/kg and further decreased by 100 and 1000 ng/kg. These effects were accompanied by changes in four important determinants of the immune-inflammatory response within the eye: (i) the B and T lymphocytes, (ii) the miRNAs pattern, (iii) the ubiquitin-proteasome system (UPS), and (iv) the M1/M2 macrophage phenotype. LPS+RvD1 treated rats showed reduced presence of B and T lymphocytes and upregulation of miR-200c-3p, miR 203a-3p, miR 29b-3p, and miR 21-5p into the eye compared to the LPS alone. This was paralleled by decreases of the ubiquitin, 20S and 26S proteasome subunits, reduced presence of macrophage M1, and increased presence of macrophage M2 in the ocular tissues. Accordingly, the levels of the cytokine TNF-α, the chemokines MIP1-α and NF-κB were reduced.

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SOCS-1 Mediates Ubiquitylation and Degradation of GM-CSF Receptor

Cited by 21 publications

References 25 publications

NK cell–derived GM-CSF potentiates inflammatory arthritis and is negatively regulated by CIS

NK cell–derived GM-CSF potentiates inflammatory arthritis and is negatively regulated by CIS

Mechanism of suppressors of cytokine signaling 1 inhibition of epithelial-mesenchymal transition signaling through ROS regulation in colon cancer cells: suppression of Src leading to thioredoxin up-regulation

Protection from Endotoxic Uveitis by Intravitreal Resolvin D1: Involvement of Lymphocytes, miRNAs, Ubiquitin‐Proteasome, and M1/M2 Macrophages

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