Host: Yogesh Kulathu

Venue: MSI Small Lecture Theatre, SLS

Abstract:

Ubiquitination is achieved through a co-ordinated enzymatic cascade of E1, E2, and E3 ligases. E1 ubiquitin activating enzymes are the initiators of ubiquitination. In most metazoans two E1 ubiquitin activating enzymes exist: UBA1 and the non-canonical E1, UBA6. Recently, we and others have discovered that the E2 and regulator of cell death and development, BIRC6, functions exclusively with UBA6. Both UBA6 and BIRC6 are essential for normal development and brain specific UBA6 knockout mice display neurological disorders. Despite their functional importance, how E2 ubiquitin-conjugating enzymes function exclusively with UBA6 is not understood. Through trapping stable complexes of E2s receiving ubiquitin from UBA6 we are uncovering the molecular determinants of E2 specificity. Our work will provide the fundamental molecular understanding crucial for investigating the non-canonical ubiquitination pathway in cellular processes.

Bio:

I completed my PhD at the University of Leicester under the supervision of Professor Peter Moody learning the dark arts of protein crystallography. I then moved to the University of Liverpool where I was a postdoc with Dr Igor Barsukov and Professor Lu-Yun Lian using NMR and crystallography to study the cell adhesion protein Talin. A collaboration with Professors Mike Clague and Sylvie Urbé in Liverpool ignited my interest in the small protein, ubiquitin. This led me to join the lab of Dr David Komander at the MRC Laboratory of Molecular Biology, Cambridge, where I became an Investigator Scientist. In 2018 I established my independent group in the Department of Biochemistry with an MRC Career Development Award.

Host: Dr Megan Bergkessel 

Venue: Sir Kenneth & Lady Noreen Murray Seminar Room CTIR 2.84

Abstract  

In this talk, I discuss the dietary preferences of an opportunistic human pathogen, Pseudomonas aeruginosa. This organism exhibits an exquisite predilection for colonizing soft tissues in the body, although it seems to have a particular soft spot for the airways, especially among individuals (such as those with cystic fibrosis (CF)) who are predisposed towards infection. Quite why it likes the airways so much is still not entirely clear, although a major contributory factor is the abundance of fatty acid derivatives at that site - and P. aeruginosa loves fatty acids. Unlike E. coli - which has more of a sweet tooth, and generally eschews fatty acids in favour of carbohydrates - Pseudomonas aeruginosa encodes no fewer than six pathways of beta-oxidation. However, these pathways all converge at a common "pinchpoint" (the fatty acyl-CoA dehydrogenase-catalyzed reaction); here, we identify the acyl-CoA dehydrogenases that do the job (and there are >20 homologues encoded by P. aeruginosa to choose from there), and show how judicious swapping of residues in the selectivity filter of the enzymes can radically change their substrate specificities. We also show that the organism is geared up to maximize use of the acetyl-CoA thus generated, becoming critically dependent on proper functioning of the glyoxylate shunt in infection scenarios. These are not esoteric observations either: they are important because P. aeruginosa uses "nutritional cues" to regulate the expression of clinically-relevant phenotypes such as virulence and AMR, and this too will be discussed. 

Venue: MSI Small Lecture Theatre

Host:  Dr David Murray

Abstract

Cellular and organismal growth depend heavily on the PI3K/Akt signaling pathway. Dysregulation of the pathway is observed in cancer, overgrowth disorders, and metabolic disease. The mechanisms that ensure the timely activation and inactivation of Akt are therefore critical to organismal homeostasis and therapeutically relevant in the treatment of disease. In the first part of my talk, I will describe the mechanism by which Akt is turned on by PIP3, the signaling lipid generated by growth factor-mediated activation of PI3K. In the second part, I will present evidence that PHLPP, a phosphatase previously reported to inactivate Akt, is, in fact, a pseudophosphatase and that cancer genomics do not support a role for PHLPP in cancer. Finally, I will present some evolutionary clues as to the real biological function of PHLPP.

Venue: Small Lecture Theatre, MSI

Hosts: Dr Mattie Pawlowic & Dr Henry McSorley

Bio 

I obtained my PhD in the lab of Dr. Amit Sharma at ICGEB, New Delhi, India, in structural biology and small molecule inhibitor discovery in human malaria. After PhD, I moved to Prof. Matt Higgins’ lab at the University of Oxford for my postdoc in structural parasitology. In the Higgins lab, I study host-parasite protein-protein interactions to understand the mechanisms underlying parasite resilience to the host. In particular, in collaboration with Dr Henry McSorley’s research team, I have studied how helminths modulate immunity. My long-term goal is to use mechanistic understanding of molecular host-parasite interactions to therapeutically impact parasitic diseases in humans and livestock.  

Abstract  

Helminths, such as H. polygyrus, aKect IL-33-dependent type 2 immunity by secreting two distinct, three-membered, CCP-domain protein families, HpARI and HpBARI. These proteins modulate IL-33 signalling by preventing IL-33 from binding to its receptor, ST2. Understanding how HpARI and HpBARI target IL-33:ST2 signalling is the central focus of this talk. I will reveal how HpARI and HpBARI function using structural biology (X-ray and cryo-EM) combined with biophysical and immunological methods. HpARI2 is monomeric and contains three CCP-domain-containing (CCP1-3), which contribute to IL-33 binding. Structure-guided in vivo studies confirm two key features of the HpARI2 function: i) a ‘large loop’ (CCP3) competitively blocks IL-33 access to ST2; ii) an electropositive CCP1 module that governs the half-life HpARI2 via heparan sulphate or DNA binding, prolonging immunosuppression. By contrast, the HpBARI are ST2-binding, trimeric molecules that directly blocks access of IL-33 and the signalling co-receptor to ST2. Ultimately, through these mechanisms HpARI and HpBARI proteins promote parasite survival and reduce host asthma. 

 Venue: Sir Kenneth and Lady Noreen Murray Room, CTIR 2.84 

Host: Professor Doreen Cantrell

Bio

After completing her studies in Molecular Biology at the University of Zurich and at the Swiss Federal Institute of Technology, Zurich, Greta Guarda carried out her PhD on T cell[1]mediated immunity at the Institute for Research in Biomedicine (IRB), Bellinzona. In 2007, she joined as a post-doc the University of Lausanne. During these years, she focused her research on NOD-like receptors and inflammasome regulation. Thanks to the award of a Swiss National Science Foundation professorship and a European Research Council starting grant, she established her independent research group in 2012.

She joined the IRB as Group Leader in 2018 and is Full Professor at the Università della Svizzera italiana, where she became Vice-Dean of Research in 2021. Her group kept a strong interest in NOD-like receptors involved in antigen presentation and in the study of selected genes impacting the response by T and natural killer cells. Currently, she is member of the SNSF Evaluation panel "Biology and Medicine division" and president elect of the Swiss Society for Allergology and Immunology (SSAI), while she has been member of the Federal Ethics Committee on Non-Human Biotechnology and of the Swiss Academy of Sciences, Forum for Genetic Research. For her scientific contributions, she was awarded the Premio Fondazione Dr. Ettore Balli 2018, the Pfizer Research Prize 2019, and the Friedrich Miescher Award 2020.

Online via Microsoft Teams

Host: Dr Henry McSorley  

Abstract 

Uncontrolled regeneration leads to neoplastic transformation. Barrier epithelia, such as the intestine, undergo continuous homeostatic and damage-induced tissue renewal and thus need to be tightly regulated to prevent neoplastic transformation, suggesting pathways that disengage tumour growth from regenerative processes must exist. By mining RNAseq datasets from two intestinal damage models and using pharmacological, transcriptomics, and genetic tools we identified liver X receptor (LXR) pathway activation as a tissue adaptation to damage that reciprocally regulates intestinal regeneration and tumorigenesis. Using single-cell and spatial transcriptomics, intestinal organoids, and gain and loss of function experiments, we demonstrated that LXR activation in intestinal epithelial cells induces amphiregulin (Areg) that boosts regenerative responses. Notably, when challenged for tumorigenesis LXR activation triggered adaptive immunity dependent anti-tumour responses. Thus, our work reveals a novel mode of epithelial adaptation to damage where LXR functions as a rheostat that promotes tissue repair while limiting tumorigenesis. 

Our findings on unlinking regeneration and tumorigenesis pave the way for innovative pro-regenerative therapies. This is particularly relevant in conditions such as inflammatory bowel disease (IBD), where existing anti-inflammatory treatments often prove inadequate. Building on these foundations, my overarching goal as an independent group leader is to develop an interdisciplinary research program focused on a novel framework for tissue regeneration while reducing tumour risks. In the short term, I plan to integrate epithelial memory and cell-fate changes into a clinical drug discovery pipeline targeting improved tissue regeneration in IBD. In the long term, these efforts may also provide insights into tissue dysfunction in conditions like age-related decline in regeneration and increased tumorigenesis. 

Venue: Small Lecture Theatre, MSI

Host: Manu De Rycker

Abstract

Meningitis caused by the fungal pathogen Cryptococcus neoformans affects half a million people and kills over 181,000 annually, mostly people with weakened immunity, such as those with cancer, organ transplant recipients and HIV/AIDS patients. We need to understand the strategies used by this fungus to cause disease and use this information to develop new antifungal drugs against Cryptococcus neoformans. Cryptococcus is unique among serious fungal pathogens of humans by the fact that it is enveloped by two sugar coats: the capsule and the cell wall. Both the capsule and the cell wall contribute to Cryptococcus virulence. I am interested in the cell wall because it is absent in mammals and could be a great target for new antifungal drugs.

Fungi such Candida and Aspergillus spp. respond to Echinocandins and Fluconazole by altering their cell wall composition. It is not known whether Cryptococcus modifies it cell wall in response to antifungal drugs treatment and whether these modifications contribute to antifungal drug resistance. In this presentation, I will first discuss why it is important to study Cryptococcus and then present our work on how Cryptococcus neoformans alters it cell wall composition when exposed to antifungal drugs currently used to treat Cryptococcus infection.