A pinboard by
Katherine Edwards

PhD Student, Queen's University Belfast


Investigating novel roles for SOCS proteins during inflammation.

The innate immune system, which forms the first line of defence from the external environment, induces inflammation in response to injury or infection. Macrophages, an innate immune cell, are recruited by signals released from the site of injury or infection. Once at the site, macrophages orchestrate the immune response tailored to the type of infection and injury enabling resolution and restoration of homeostasis.

Inflammasomes represent innate immune signalling complexes that play a vital role in the induction of inflammation and wound healing. They are activated within macrophages upon detection of infection or injury. This leads to secretion of inflammatory cytokines enabling recruitment of more immune cells and the establishment of a greater immune response.

Unfortunately, when inflammasome activity is dysregulated this can lead to recurrent attacks of fever with systemic inflammation. As existing therapies are often unsuccessful in patients with dysregulated inflammasome activity, current research has focused on understanding the regulation of inflammasome activity to identify novel targets or signalling pathways that can be modulated in patients to relieve symptoms.

Recently, post-translational modifications have been identified to play an important role in regulating inflammasome activity, in particular the process of ubiquitination (enables targeting of proteins for degradation, and activation). Therefore, it is of great value to identify E3 ligases (enable ubiquitination) or complexes that may regulate ubiquitination of inflammasome components.

My research investigates the role of the E3 ubiquitin ligases suppressor of cytokine signalling (SOCS) proteins in regulating inflammasome activity in response to inflammatory stimuli, such as bacterial infection.

To accomplish this I utilise various SOCS-deficient mouse models that allow me to characterise the effects of SOCS2 and SOCS3 deficiencies in inflammation and infection.

In the future this knowledge will enable us to informatively target specific aspects of inflammatory pathways and infection to treat disease and clear infection.


SOCS proteins: negative regulators of cytokine signaling.

Abstract: Cytokines regulate the growth and differentiation of cells by binding to cell-surface receptors and activating intracellular signal transduction cascades such as the JAK-STAT pathway. Cytokine signaling is negatively regulated with respect to both magnitude and duration, and it is now clear that the suppressor of cytokine signaling (SOCS) family of proteins (SOCS1-SOCS7 and CIS) contributes significantly to this process. Transcripts encoding CIS, SOCS1, SOCS2, and SOCS3 are upregulated in response to cytokine stimulation, and the corresponding SOCS proteins inhibit cytokine-induced signaling pathways. SOCS proteins therefore form part of a classical negative feedback circuit. SOCS family members modulate signaling by several mechanisms, which include inactivation of the Janus kinases (JAKs), blocking access of the signal transducers and activators of transcription (STATs) to receptor binding sites, and ubiquitination of signaling proteins and their subsequent targeting to the proteasome. Gene targeting has been used to generate mice lacking socs1, socs2, or socs3, in order to elucidate the physiological function of these SOCS family members. The analysis of socs1(-/-) mice has revealed that SOCS1 plays a key role in the negative regulation of interferon-gamma signaling and in T cell differentiation. Socs2(-/-) mice are 30%-40% larger than wild-type mice, demonstrating that SOCS2 is a critical regulator of postnatal growth. Additionally, the study of embryos lacking socs3 has revealed that SOCS3 is an important regulator of fetal liver hematopoiesis. The biological role of other SOCS proteins remains to be determined.

Pub.: 13 Sep '01, Pinned: 07 Oct '17

Implication of inflammatory signaling pathways in obesity-induced insulin resistance.

Abstract: Obesity is characterized by the development of a low-grade chronic inflammatory state in different metabolic tissues including adipose tissue and liver. This inflammation develops in response to an excess of nutrient flux and is now recognized as an important link between obesity and insulin resistance. Several dietary factors like saturated fatty acids and glucose as well as changes in gut microbiota have been proposed as triggers of this metabolic inflammation through the activation of pattern-recognition receptors (PRRs), including Toll-like receptors (TLR), inflammasome, and nucleotide oligomerization domain (NOD). The consequences are the production of pro-inflammatory cytokines and the recruitment of immune cells such as macrophages and T lymphocytes in metabolic tissues. Inflammatory cytokines activate several kinases like IKKβ, mTOR/S6 kinase, and MAP kinases as well as SOCS proteins that interfere with insulin signaling and action in adipocytes and hepatocytes. In this review, we summarize recent studies demonstrating that PRRs and stress kinases are important integrators of metabolic and inflammatory stress signals in metabolic tissues leading to peripheral and central insulin resistance and metabolic dysfunction. We discuss recent data obtained with genetically modified mice and pharmacological approaches suggesting that these inflammatory pathways are potential novel pharmacological targets for the management of obesity-associated insulin resistance.

Pub.: 15 Jan '13, Pinned: 31 Aug '17

Role of Linear Ubiquitination in Health and Disease.

Abstract: The covalent attachment of ubiquitin to target proteins is one of the most prevalent post-translational modifications, regulating a myriad of cellular processes including cell growth, survival, and metabolism. Recently a novel RING E3 ligase complex was described termed LUBAC (Linear Ubiquitin Assembly Complex), which is capable of connecting ubiquitin molecules in a novel head-to-tail fashion via the N-terminal methionine residue. LUBAC is a heteromeric complex composed of HOIL-1 (Heme-Oxidized Iron responsive element binding protein 2 ubiquitin Ligase-1), HOIP (HOIL-1-Interacting Protein), and SHARPIN (Shank-Associated RH domain-Interacting Protein). The essential role of LUBAC-generated linear chains for activation of NF-κB signaling was first described in the activation of TNF-α-receptor signaling complex. A decade of research has identified additional pathways that utilize LUBAC for downstream signaling, including CD40 ligand and the IL-1β receptor as well as cytosolic pattern recognition receptors including NOD2, RIG-I and the NLRP3 inflammasome. Even though the three components of the complex are required for full activation of NF-κB, the individual components of LUBAC regulate specific cell type and stimuli dependent effects. In humans, autosomal defects in LUBAC are associated with both autoinflammation and immunodeficiency with additional disorders described in mice. Moreover, in the lung epithelium, HOIL-1L ubiquitinates target proteins independently of the other LUBAC components, providing another layer of complexity to the function and regulation of LUBAC.

Pub.: 06 Feb '16, Pinned: 31 Aug '17