Cambridge Institute for Medical Research

COVID-19 UPDATE

The CIMR has reopened for research on Monday June 15th, following detailed, University-approved protocols to protect our staff and students, who are the heart of our institution. We will continue to work from home whenever possible, but critical lab experiments are now starting again. We are pleased to see some normality return, but also recognise that the COVID-19 crisis and its impacts are far from over, and we will continue to adjust working practice in the weeks and months ahead. Deliveries aside, our building remains closed to external visitors. For general enquiries, please use cimr-reception@lists.cam.ac.uk or phone 01223 762322. Email continues to be the best way to contact other CIMR staff and students. COVID-19 has demonstrated on a global scale the impact that disease has on patients, on families and communities. Our research contributes to understanding the molecular mechanisms of a range of human diseases, and these diseases have not paused during lockdown. We are delighted that our talented researchers can now resume their critical work at the lab bench again. Thanks to all our staff and students for the amazing support and community spirit and support during this difficult time.

Our strategy

CIMR is a unique partnership between basic and clinical research, aiming to understand the cellular basis of disease. Our goal is to create an inspiring environment in which outstanding scientists can excel. By providing state-of-the-art core facilities and support for our researchers, we foster new collaborations that spark discoveries about fundamental cellular processes and their relevance in disease.

Research Advance

Reversible protein tyrosine phosphorylation by kinases and phosphatases is a key component of cellular signalling. CIMR PhD student Iain Hay and colleagues from the labs of co-supervisors Janet Deane (CIMR) and Hayley Sharpe (Babraham), together with Maja Koehn (Freiburg) have published in Nature Communications on the structure and function of the receptor protein tyrosine phosphatase PTPRU. X-ray crystallography and biochemical analysis reveal a novel mechanism by which PTPRU regulates tyrosine phosphorylation indirectly through its two catalytically inactive phosphatase domains. By competing with related, active receptor tyrosine phosphatases, PTPRU acts to ‘protect’ the phosphotyrosines of shared substrates. This process is likely to be important for fine-tuning the formation and stability of cell-cell junctions.

Research Advance

Nutrient depletion is one of several triggers of autophagy in cells. Previous work by Sung Min Son and Rubinsztein lab colleagues showed how cells respond to levels of the essential amino acid leucine through its metabolite acetyl co-enzyme A (AcCoA) and the mTORC1 complex, a master regulator of cellular growth and metabolism, and a negative regulator of autophagy. A new paper in Nature Communications extends this sensing mechanism to autophagy regulation. Under normal conditions, autophagy is suppressed through AcCoA- and EP300- dependent acetylation of raptor, which activates mTORC1. When cells are deprived of leucine, AcCoA levels decrease, thereby allowing autophagy to be activated through the converse process.

Research Advance

Millions of naïve T cells with different TCRs may interact with a peptide-MHC ligand, but very few will activate. This fine control is orchestrated using a limited set of intracellular machinery. Publishing in eLife, Dr Claire Ma from the Wellcome Clinical PhD programme and Dr Arianne Richard, a joint postdoctoral Fellow from the Griffiths and Marioni labs investigated how changes in stimulation strength alter the programme of signalling events leading to T cell activation. Using mass cytometry to simultaneously measure multiple signalling pathways during activation of murine CD8+ T cells, they found a programme of distal signalling events that is shared, regardless of the strength of TCR stimulation. Moreover, the relationship between transcription of early response genes Nr4a1 and Irf8 and activation of the ribosomal protein S6 is also conserved across stimuli. Instead, stimulation strength dictates the rate with which cells initiate signalling through this network. These data suggest that TCR-induced signalling results in a coordinated activation program, modulated in rate but not organization by stimulation strength.

Research Advance

Optineurin is a multifunctional protein important in autophagy and regulation of immune signalling. Defects in optineurin gene function are linked to a number of human diseases including motor neuron disease. Dr Thomas O’Loughlin and CIMR colleagues from the Buss lab, together with collaborators from UCL have shown in the Journal of Cell Science that downstream of a signal from viral RNA, optineurin moves to distinct foci close to the Golgi complex. This process results in the downregulation of the NFκB and IRF3 pathways, inflammatory cytokine secretion, and therefore a reduced immune response. Ultrastructural analysis of these foci reveals that this compartment consists of a tight cluster of small membrane vesicles, which appear positive for the autophagy protein ATG9A. Functional proteomics identifies part of the machinery sequestered at this viral RNA-induced compartment, while the cellular impact of disease-causing mutations in optineurin are also described.

Research Advance

With key roles in normal cellular homeostasis and a range of diseases, autophagy is mediated by autophagosomes. Using insights from a rare muscle-wasting disease, Dr Claudia Puri from the CIMR’s Rubinsztein Laboratory and colleagues present a new model for the subcellular origins of autophagosomes and their regulation. Mutations in the DNM2 (dynamin 2) gene cause some forms of autosomal dominant centronuclear myopathy (AD-CNM). Puri et al demonstrate in Developmental Cell that autophagosomes can be ‘snipped off’ tubular recycling endosome membranes in a process which requires DNM2, but which can be defective in AD-CNM.

Research Advance

The identities and functions of different white blood cell types are determined in part by their cell-surface proteins - which can also be important markers in the clinic. Monocytes have key roles in inflammatory and immune responses to infection, partly by differentiating into localised tissue macrophages and dendritic cells. Using known surface marker proteins, circulating monocytes are classified into three subtypes (classical, intermediate and non-classical), each with differing biological functions and disease associations. Clinician Dr Ben Ravenhill and colleagues in CIMR’s Weekes Lab and Proteomics Facility present in Scientific Reports the first quantitative proteomic analyses of surface proteins from these monocyte subtypes. Using selective cell surface biotinylation and MS3 mass spectrometry, this study provides new insights into the basis of monocyte diversity and function.

Research Advance

Human cytomegalovirus persistently infects most people worldwide and is a major cause of disease in transplant recipients and newborns. However, the functions of many viral genes are unknown. Recently, Luis Nobre and colleagues from the Weekes lab published in eLife a mass spectrometry-based interactome analysis for 171 human cytomegalovirus proteins, identifying a network of >3,400 virus-host and >150 virus-virus protein-protein interactions. This provided new insights into virally-induced host protein degradation, protein domain associations and viral protein functions. Furthermore, the previously uncharacterised ORFL147C protein was found to interact with elements of the mRNA splicing machinery, while a mutational study suggested its importance in viral replication.

Research Advance

The ability of cells to clear unwanted proteins and organelles through autophagy is a requirement across biology. Conversely, the accumulation of misfolded, toxic proteins inside cells is a hallmark of a number of human diseases. In the CIMR, Professor David Rubinsztein’s lab researches autophagy and how it relates to neurodegenerative diseases such as Huntington’s, Alzheimer’s and Parkinson’s. A new paper published in eLife uncovers a regulatory mechanism common to mammalian cells and C.elegans worms: the role of the microRNA miR-1, which activates autophagy through reducing expression of a Rab GTPase-activating protein known as TBC-7 in the worm and TBC1D15 in mammals. The reduction in TBC-7 / TBC1D15 in turn increases the activity of Rab7, a positive regulator of autophagy. This mechanism was tested in a worm model of Huntingtin polyQ toxicity by collaborators in Prof. Roger Pocock’s lab, from the Monash Biomedicine Discovery Institute, and in mammalian cells by Prof. Rubinsztein’s lab. Interferon-beta was shown to activate this process in the latter model, with the potential for therapeutic application.

New Wellcome Trust Fellowship award at CIMR

Congratulations to Dr Chloe Johnson for being awarded a Sir Henry Wellcome Postdoctoral Fellowship at the CIMR. With Professor Folma Buss, Chloe will be investigating the spatial and temporal regulation of immune-specific myosin motors. In collaboration with Ludwig Maximilian University of Munich and University of Kent, Chloe will use a multidisciplinary approach to uncover the role of these myosins in neuroinflammation.

Senior Academic Promotion

Congratulations to CIMR Principal Investigator Dr Mike Weekes on his promotion to University Reader.

New Wellcome Trust Fellowship award at CIMR

We are pleased to welcome Dr Anna Helena Lippert as Sir Henry Wellcome Postdoctoral Fellow at the CIMR. With Professor Gillian Griffiths as sponsor, Anna’s four year project will focus on visualisation of mechanical forces within T cells as they kill targets.

Published commentary on haemoglobin and COVID-19.

There was some recent interest in a preprint article (https://tinyurl.com/rsngw5r) which used computer modelling (but no experimental data) to propose that the COVID-19 virus ‘attacks’ haemoglobin in the blood of patients. The preprint has been the basis for claims that COVID-19 is not actually a lung disease. In response, the CIMR’s Prof. Randy Read has provided a follow-up critique in the same preprint repository which argues that from bioinformatic, thermodynamic and structural biology perspectives, the methods from the original article were fatally flawed (https://tinyurl.com/y9vm8feq). As a result, there is no reason to suspect that the virus attacks haemoglobin.

Professor Michael Wakelam 1955-2020

We were shocked and saddened by the loss of Michael Wakelam following a suspected COVID-19 infection. Michael was a renowned scientist and a kind, thoughtful and inspiring colleague. In addition to his Director’s role at Babraham, Michael held an Honorary Professorship at the University of Cambridge Clinical School, and was a long-term supporter and friend to CIMR with a great interest in cell biology and our research. Many CIMR researchers enjoyed scientific collaborations and discussions with Michael, and he will be sadly missed. Our deepest condolences are extended to Michael’s family.

Wellcome Trust Senior Research Fellowship for CIMR Principal Investigator

Congratulations to CIMR’s Dr Janet Deane for being awarded a highly prestigious Wellcome Trust Senior Research Fellowship to study how glycosphingolipids modulate protein trafficking in the cell. Using powerful multidisciplinary approaches Dr Deane’s research will identify how imbalances in glycosphingolipid metabolism cause a range of devastating early-onset neurodegenerative diseases.

CIMR-generated tools used in a new structural biology study of coronavirus (2019-nCoV)

A range of different research expertise is needed in the global response to the ongoing 2019-nCoV outbreak. This week, researchers from the University of Texas at Austin and the (US) National Institutes of Health published in Science a detailed structure of the coronaviral Spike glycoprotein, 2019-nCoV S. This protein is found on the outside of the virus and is thought to enable it to enter and infect its human host cells. 2019-nCoV S is therefore a key target for the development of vaccines and therapeutic antibodies, and efforts to develop such treatment approaches will be facilitated greatly by a detailed molecular understanding of its structure and mechanisms of action. In recent years there has been considerable progress in the technologies available to determining protein structure, particularly the advent of cryo-electron microscopy, or cryo-EM, which is significantly changing the rate at which new structures can be solved. Accompanying this is the need for software to provide accurate interpretation of highly complex structural data through modelling algorithms. At the CIMR, Professor Randy Read’s group has provided key components to software platforms that have been widely-used in generating tens of thousands of published protein structures. Both ISOLDE (developed by Dr Tristan Croll) and the PHENIX platform to which the Read lab has contributed were cited in the recent 2019-nCOV S structure paper, helping to enable and accelerate the rapid generation of these important data.

New Wellcome Trust Fellowship award for CIMR early-career researcher

Congratulations to Dr Jonny Nixon-Abell who was awarded a Sir Henry Wellcome Postdoctoral Fellowship at the CIMR. With Professor Peter St George-Hyslop as sponsor, Jonny’s four-year project is ‘to explore mechanisms of protein recruitment to specific organelle subdomains in the context of health and neurodegenerative disease’. He will focus on interactions between endoplasmic reticulum proteins and the functional organisation of a group of cytosolic partners.

Medal Lecture from CIMR Principal Investigator

Congratulations to the CIMR’s Professor David Rubinsztein for his award of the Pathological Society’s Goudie Medal. This award is to acknowledge ‘seminal contributions to pathological science and the understanding of disease mechanisms’. Prof. Rubinsztein presented the 15th Goudie Lecture on ‘Autophagy and Neurodegeneration’ at the Society’s winter meeting on January 21st 2020.

Meeting prize for CIMR PhD Student

Congratulations to Lisa Neidhardt, a CIMR PhD Student in David Ron’s laboratory, who was awarded first prize for her talk “Unstructured regions in IRE1α specify BiP-mediated destabilisation of the luminal domain dimer and repression of the UPR” at the joint UK / Netherlands Chaperone Club anniversary meeting on December 17th in Manchester.

2019 CIMR Research Retreat

CIMR held its research retreat on November 29th at the Wellcome Genome Campus Conference Centre. The scientific programme was delivered by our excellent PhD students and post-doctoral research associates. Congratulations to the prize winners, and thanks to all who took part and made it a success.