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Cambridge Institute for Medical Research

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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.

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Research Advance

Over the centuries, malaria has selected for many natural human genetic variants such as sickle haemoglobin that provide protection against severe disease. One such variant, Dantu, codes for an unusual hybrid glycophorin protein on the surface of red blood cells and is only found at high frequency in coastal East Africa. Determining how Dantu protects against malaria is the focus of a new paper published in Nature by a multidisciplinary team featuring multiple CIMR authors from the Rayner and Weekes labs, together with researchers from Cambridge’s Cavendish Laboratory, the KEMRI Research Institute (Kenya) and the Wellcome Sanger Institute. The paper’s key finding is that membranes of red blood cells from people carrying the Dantu variant are under increased biophysical tension, which makes them more resistant to invasion by the malaria parasite. Tension varies naturally across all red blood cells, and this work identifies for the first time a tension threshold above which invasion routinely fails, pointing to novel ways to treat this deadly disease.

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Research Advance

Hypoxia-inducible factor (HIF) 1α is a key orchestrator of a wide range of responses to changes in cellular oxygen levels. Dr Natalie Burrows and colleagues from Prof. Patrick Maxwell’s lab at CIMR, together with other co-authors, have reported in Nature Immunology an essential role for HIF1α in the early development of B cells. Deep inside bone marrow, elevated HIF1α activity acts a developmental brake within immature B cells- which is released upon their transition to a less hypoxic state, enabling their subsequent departure from the bone marrow and development. This involves a key tolerance mechanism, a process that limits the survival of B cells that recognise self. Additional experiments in mice using a pharmacological activator of the HIF pathway support this link further, opening up potential therapeutic applications in certain autoimmune conditions or B cell malignancies.

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Research Advance

A powerful example of how researching rare genetic variants can provide much wider insights was published recently in a multi-disciplinary, Cambridge-led study of childbirth pain. Together with Dr Michael Lee and colleagues at the Dept. of Anaesthetics, Prof. Geoff Woods’ CIMR team found a rare variant of the KCNG4 gene which was over-represented in a group of women who asked for no pain relief during labour. KCNG4 encodes for the voltage-gated potassium channel subunit Kv6.4. Dr Ewan St. John Smith’s group at the Dept. of Pharmacology then discovered that Kv6.4 was almost exclusively expressed in uterine nociceptors, and that the rare variant of Kv6.4 modulated potassium channels resulting in reduced nociceptor activity. Labour pain is the usual reason given by women for the increasing rates of epidurals for delivery and elective Caesarean sections; this work suggests that systemic delivery of Kv6.4 antagonist could be useful analgesic for labour – without the adverse effects associated with currently available local anaesthetics which occur even when administered via the epidural route.

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Research Advance

Programmed cell death pathways can be activated as a defence mechanism in cells infected with viruses to reduce further viral spread. These pathways can be either necroptotic (which trigger local inflammatory responses) or apoptotic (which are non-inflammatory), but both can be targeted by viral inhibitor proteins. Final-year CIMR PhD student Alice Fletcher-Etherington in the Weekes lab, together with other colleagues have published in PNAS on how human cytomegalovirus (HCMV) can subvert host cell death pathways to enhance its cellular infectivity. From proteomic screens, this new paper shows how the HCMV protein pUL36 targets MLKL, a key human cell regulator of necroptosis, for proteasome degradation. This mechanism is combined with pUL36’s anti-apoptotic action, making it a ‘dual-death inhibitor’ and a potential target for anti-HCMV therapy.

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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.

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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.

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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.

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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.

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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.

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Award for rare disease research at CIMR

Congratulations to Dr Joseph Chambers of the Marciniak Lab, one of two winners of the 18th Annual Alpha-1-Antitrypsin Laurell’s Training Award. This global award is to support early-career researchers working on alpha-1-antitrypsin deficiency. Joseph’s project is entitled ‘Effects of alpha-1 antitrypsin polymerisation on organelle structure and fluidity in hepatocytes’, and will be supported with €50,000 from Grifols S.A.

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CIMR spin-out company starts first clinical trial

Z Factor Ltd have announced that dosing has begun in a Phase I study of ZF874, their first-in-class, small molecule drug. This was discovered from research at Prof. Jim Huntington's laboratory in CIMR as a potential treatment for alpha-1-antitrypsin deficiency (AATD). Most forms of this genetic disease are caused by the misfolding and accumulation of the Z variant of alpha-1-antitrypsin in liver cells. As well as liver disease, there is also downstream lung damage in AATD. ZF874 is designed specifically to correct the misfolding of Z-AAT. Once the first stage of this safety and dosing study is complete in healthy volunteers, it will be extended to AATD patients. Results are expected by the end of 2020.


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.

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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.


Coronavirus

Postgraduate Open Day

New publications

Rayner lab (Nature, 2020)
Red blood cell tension protects against severe malaria in the Dantu blood group

Maxwell lab (Nature Immunology, 2020)
Dynamic regulation of hypoxia-inducible factor-1α activity is essential for normal B cell development

Owen lab in collaboration with the Briggs lab, LMB (Science Advances, 2020)
Architecture of the AP2/clathrin coat on the membranes of clathrin-coated vesicles

Weekes lab (PNAS, 2020)
Human cytomegalovirus protein pUL36: A dual cell death pathway inhibitor

Woods lab (Cell Reports, 2020)
Human Labor Pain Is Influenced by the Voltage-Gated Potassium Channel KV6.4 Subunit

Deane lab (Nature Communications, 2020)
The receptor PTPRU is a redox sensitive pseudophosphatase

Rubinsztein lab (Nature Communications, 2020)
Leucine regulates autophagy via acetylation of the mTORC1 component raptor

Rubinsztein lab in collaboration with the Goldberg lab, Harvard (PNAS, 2020)
cGMP via PKG activates 26S proteasomes and enhances degradation of proteins, including ones that cause neurodegenerative diseases

Griffiths lab (eLife, 2020)
Stimulation strength controls the rate of initiation but not the molecular organization of TCR-induced signalling

Buss lab (Journal of Cell Science, 2020)
OPTN recruitment to a Golgi-proximal compartment regulates immune signalling and cytokine secretion

Rubinsztein lab (Developmental Cell, 2020)
A DNM2 Centronuclear Myopathy Mutation Reveals a Link between Recycling Endosome Scission and Autophagy

Buss lab (Biology of Reproduction, 2020)
Myosin VI maintains the actin-dependent organization of the tubulobulbar complexes required for endocytosis during mouse spermiogenesis

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

Buss lab (Traffic, 2020)
Ultrastructural insights into pathogen clearance by autophagy

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