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Cambridge Institute for Medical Research

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COVID-19 UPDATE

Together with the rest of the University of Cambridge https://www.cam.ac.uk/coronavirus, the CIMR building is shutting down for normal activities from 5pm, Friday 20th March 2020 until further notice. Our building won’t be open to visitors and meetings, and most staff will be working from home, and contactable by email. For any general enquiries, email cimr-reception@lists.cam.ac.uk ; please show patience as responses may not be as prompt as normal. We recognise that the current COVID-19 situation is a very difficult, uncertain, and in some cases, tragic time for people. All of us have roles to play in response to this crisis, but our admiration, gratitude and support go to everyone who is working hard, often at risk to themselves, to help patients and to keep wider society running as well as it can. This includes our colleagues at the Cambridge University Hospitals NHS Foundation Trust. We hope that everyone stays well and safe.


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.

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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.

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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.

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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.

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Research Advance

Cytotoxic T lymphocytes (CTLs) play a critical role in the immune system, recognising and destroying virally infected and cancer targets with remarkable specificity. CTLs are particularly important right now, with new immunotherapies focused on harnessing the cytotoxic potential of these cells to combat cancer. Research in the Griffiths lab aims to identify the multitude of genes that control killing and to understand the underlying cell biology that addresses the question: what makes a good killer? The lab’s most recent paper in the Journal of Clinical Investigation follows the identification of a small number of immunodeficient patients who carry mutations in the gene for actin-related protein complex 1B (ARPC1B) and are susceptible to severe infections. Dr Lyra Randzavola and colleagues show that CTLs require ARPC1B for normal growth and proliferation during an immune response. These findings could explain why patients lacking ARPC1B struggle with chronic viral infections, and shed light on the complex interplay between the actin cytoskeleton and vesicle trafficking in CTLs.

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Research Advance

Professor David Ron’s lab researches how cells react to stresses in protein homeostasis via the Integrated Stress Response (ISR). Dr Heather Harding and colleagues from the Ron Lab, together with collaborators at the Wellcome Trust Sanger Institute and MRC Laboratory of Molecular Biology have published in eLife on how mammalian cells activate the ISR when being starved of amino acids. Using genetic screens and in vitro biochemistry, the authors show that under amino acid starvation, the P-stalk (a ribosome component) activates the protein kinase GCN2, which then phosphorylates eIF2 alpha, resulting in the downstream ISR pathway towards cellular recovery.

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Research Advance

Mutations in the spastin gene are a principal cause of hereditary spastic paraplegia (HSP). Research from the Reid lab has provided new insights into the normal function of spastin, a microtubule-severing ATPase, and the cellular consequences of its loss in HSP. Publishing in Cellular and Molecular Life Sciences, Connell et al show, in cellular models, that spastin interacts with the ESCRT-III-associated proteins IST1 or CHMP1B to prevent cell-polarising membrane protrusions from forming. The protrusions are driven by protrudin, another spastin-interactor. This regulatory control of spastin over protrudin is lost in the absence of spastin, and therefore may contribute to HSP disease pathology.

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Research Advance

The advent of CRISPR/Cas9 technology has opened up a growing number of possibilities in genome editing. Paul Manna and Luther Davis from the Robinson and Luzio labs have published a new methodology, CRISPR/Cas9-mediated Homology-independent PCR-product Integration (CHoP-In), in the journal Traffic. Their method enables the generation of 'knock-in' cell lines expressing target proteins N-, C- or internally-tagged with EmGFP / mCherry, without a requirement for donor vectors. Instead, the reporter fusions were generated by PCR and co-transfected directly with the gRNA / Cas9 vector targeting the genes of interest. Positively-expressing cells were separated by flow cytometry and characterised (above left). This method will be used further in the Robinson lab and has already received some wider interest.

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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.


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.


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.


CIMR researcher receives recognition for influential publication output

Professor David Rubinsztein FRS has recently been highlighted by the Web of Science Group as a 2019 ‘Highly Cited Researcher’ for his research on mechanisms of autophagy and neurodegeneration. This reflects analysis by Web of Science of Prof. Rubinsztein’s research publications in the years 2008 – 2018, many of which rank in the top 1% by citations for a given research field or fields. The University of Cambridge was the highest ranking UK University by numbers of highly cited researchers from the 2019 analysis.


Coronavirus

Postgraduate Open Day

New publications

Weekes lab (Scientific Reports, 2020)
Comprehensive cell surface proteomics defines markers of classical, intermediate and non-classical monocytes

Read lab (Acta Crystallographica Section D, 2020)
Measuring and Using Information Gained by Observing Diffraction Data

Read lab (Acta Crystallographica Section D, 2020)
Factors influencing estimates of coordinate error for molecular replacement

Ron lab (eLife, 2019)
Unstructured regions in IRE1α specify BiP-mediated destabilisation of the luminal domain dimer and repression of the UPR

Weekes lab (eLife, 2019)
Human cytomegalovirus interactome analysis identifies degradation hubs, domain associations and viral protein functions

Rubinsztein lab (eLife, 2019)
Interferon-β-induced miR-1 alleviates toxic protein accumulation by controlling autophagy

Ron lab (eLife, 2019)
The ribosomal P-stalk couples amino acid starvation to GCN2 activation in mammalian cells

Griffiths lab (Journal of Clinical Investigation, 2019)
Loss of ARPC1B impairs cytotoxic T lymphocyte maintenance and cytolytic activity

Reid lab (Frontiers in Neuroscience, 2019)
Spastin MIT Domain Disease-Associated Mutations Disrupt Lysosomal Function

Deane lab (Wellcome Open Research, 2019)
The lipid transfer protein Saposin B does not directly bind CD1d for lipid antigen loading

Reid lab (Cellular and Molecular Life Sciences, 2019)
ESCRT‑III‑associated proteins and spastin inhibit protrudin‑dependent polarised membrane traffic

Ron lab (EMBO Journal, 2019)
An oligomeric state‐dependent switch in the ER enzyme FICD regulates AMPylation and deAMPylation of BiP

Robinson lab (Traffic, 2019)
Fast and cloning‐free CRISPR/Cas9‐mediated genomic editing in mammalian cells

Weekes lab (Communications Biology, 2019)
Quantitative comparative analysis of human erythrocyte surface proteins between individuals from two genetically distinct populations

St George-Hyslop lab (Cell, 2019)
RNA Granules Hitchhike on Lysosomes for Long-Distance Transport, Using Annexin A11 as a Molecular Tether

Siniossoglou lab (Developmental Cell, 2019)
Compartmentalized Synthesis of Triacylglycerol at the Inner Nuclear Membrane Regulates Nuclear Organization

Weekes lab (Cell Metabolism, 2019)
Epstein-Barr-Virus-Induced One-Carbon Metabolism Drives B Cell Transformation

Warren lab (Blood, 2019)
EFL1 mutations impair eIF6 release to cause Shwachman-Diamond syndrome.

Warren lab (eLife, 2019)
Mechanism of completion of peptidyltransferase centre assembly in eukaryotes

Weekes lab (Cell Reports, 2019)
Quantitative Temporal Proteomic Analysis of Vaccinia Virus Infection Reveals Regulation of Histone Deacetylases by an Interferon Antagonist

Rubinsztein lab (Nature Communications, 2019)
Felodipine ameliorates neurodegeneration in mice

Sharpe lab (eLife, 2019)
The receptor PTPRK selectively dephosphorylates junctional regulators

Ron lab (Nature Comm, 2019)
MANF anatagonizes nucleotide exchange by the enodplasmic reticulum chaperone BiP