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Cambridge Institute for Medical Research

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COVID-19 UPDATE

The CIMR remains open for research under social-distancing restrictions. 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.


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

YAP and TAZ are both transcriptional regulators with central roles in cell growth. Mariana Pavel, So Jung Park and colleagues from the Rubinsztein lab have discovered a feedback loop linking autophagy with YAP/TAZ signaling. Publishing in Nature Communications, the researchers show how alpha-catenin protein levels regulate this feedback loop. These findings explain how different cells can exhibit very different relationships between autophagy and growth pathways, highlighting a source of variation in experimental cell model and potentially guiding therapies aimed at either increasing or decreasing autophagy in different disease contexts.

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Research Advance

VCP/p97 is an evolutionarily-conserved ATPase with a role in cellular protein homeostasis and quality control. A human VCP mutation that decreases its activity causes dementia associated with tau accumulation. Dr Sandra Hill and colleagues from the Rubinsztein lab, in collaboration with AstraZeneca, have shown a new role for VCP in the initiation of autophagy. Publishing in Nature Chemical Biology, the authors demonstrate a dual mechanism by which VCP stimulates the production of PI(3)P, a key event in the generation of early autophagosomes.

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Research Advance

Publishing in the Journal of Cell Biology, Dr Hirst in the Robinson lab and co-authors show that recruitment of the AP-5 complex (that includes SPG11 and SPG15) is by coincidence detection, requiring both phosphatidylinositol 3-phosphate and Rag GTPases. The requirement for Rag GTPases places the AP-5 complex right at the heart of the signalling network that governs the cell’s response to starvation, uncovering an important link between the AP-5 complex and the mTORC1 pathway. These findings provide new insights into both the function of the AP-5 complex in normal cells and why its absence leads to spastic paraplegia, and could potentially open up new therapeutic approaches.

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Research Advance

mTORC2 is a protein complex in a network which transduces extracellular signals from growth factors into cellular responses such as growth, proliferation and nutrient metabolism. The precise mechanisms of this process are unclear. However, Dr Lidia Wrobel and colleagues from CIMR’s Rubinsztein lab demonstrate in Cell Reports that growth factors stimulate the expression of the protease USP9X, which then has a role in activating mTORC2 and downstream signalling. The protein RICTOR is needed to form the mTORC2 complex, but it can’t do so when ‘tagged’ with polyubiquitin at K274. USP9X removes the ubiquitin ‘tags’ from RICTOR, enabling the deubiquitinated RICTOR to form an active mTORC2 complex with other components. Dysregulated mTORC2 is a feature of some metabolic disorders and cancers; new mechanistic insights such as this may contribute towards understanding of these diseases and potentially guide new therapeutic approaches.

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Research Advance

The Integrated Stress Response (ISR) is a protective mechanism used by cells when they detect adverse conditions. However, prolonged activation of the ISR can occur in, and contribute to some disease states. Dampening the ISR is therefore a potential treatment strategy for such conditions. ISRIB, is an experimental tool compound that does this, and a new paper from the Ron lab at CIMR and the Ito lab at RIKEN, Japan sheds new light on its mechanism of action. Publishing in Molecular Cell, Alisa Zyryanova, Kazuhiro Kashiwagi and colleagues demonstrate that ISRIB binds a protein called eIF2B, affecting its interactions with active and inactive forms of its target, eIF2, thereby attenuating the ISR.

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Research Advance

A new paper in The American Journal of Human Genetics has been published by a UK-Italian collaboration co-led by CIMR’s Dr Evan Reid and Prof. Lucy Raymond, together with Dr Marco Tartaglia (ICRCC, Rome). Rapid whole genome sequencing of children in neonatal intensive care, combined with detailed analyses of genomic databases identified patients with a novel severe neurodevelopmental syndrome (termed CIMDAG), who all had mutations in the VPS4A gene. Dr Catherine Rodger and Dr Rachel Allison from the Reid Lab then undertook detailed molecular and cellular modelling of these mutations, including in stem cell-derived human neurons. VPS4A is a master regulator of the ‘endosomal sorting complexes required for transport’ (ESCRTs), cellular machinery that is active in many different membrane fission processes. The VPS4A mutations disrupted key cellular processes including endosomal trafficking and cell division. This research illustrates how the causes of devastating diseases can be understood by combining powerful genomics with cellular and molecular biology.

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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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CIMR researchers featuring at the 2021 Cambridge Festival

The new and online Cambridge Festival will take place from 26th March to 4th April 2021. CIMR research will be represented at two Festival events; advance booking will be essential for both: On March 27th (2-3 pm) Prof. Stefan Marciniak will present ‘The grander view: How modern microscopy illuminates a rare disease’. The event will be hosted by Alliance Française Cambridge; tickets are available here: https://www.eventbrite.co.uk/e/the-grander-view-how-modern-microscopy-illuminates-a-rare-disease-tickets-135693957279. On 31st March (7-9 pm) Dr Claudia Millán from the Read Group will explain her work on the 3D structures of proteins at her talk “Somewhere over the rainbow” at the Pride of Cambridge event, an entertaining and stimulating celebration of Cambridge’s LGBT+ researchers. Tickets can be obtained here: https://www.eventbrite.co.uk/e/pride-of-cambridge-tickets-131615628889

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CIMR researcher and COVID19 expert featured in the media

CIMR's Dr Mike Weekes is also an honororary consultant in infectious diseases at Cambridge University Hospitals NHS Foundation Trust (CUH). Dr Weekes has led COVID19 screening work to control the spread of the virus and to understand the impact of vaccination programmes on the pandemic. His most recent study showed the benefits of even a single vaccine shot in reducing the rate of positive COVID19 tests in CUH staff who had no symptoms of infection. This work was highlighted on BBC and ITV News, and many other online and print outlets.

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CIMR spin out company ApcinteX reports its first trial results in haemophilia

Both ApcinteX and the company’s lead development drug SerpinPC, resulted from a collaboration between CIMR’s Prof. Jim Huntington and haematologist Dr Trevor Baglin (formerly of Cambridge University Hospitals). The results from AP-0101, the first human trial of SerpinPC were presented today at the 14th Annual Congress of the European Association for Haemophilia and Allied Disorders. Neither the Phase 1A study with healthy volunteers, nor the Phase 1B study of people with severe haemophilia reported safety concerns. The effect of SerpinPC treatment on the number of bleeding episodes was also measured as an exploratory endpoint in the patient group, and this too looked encouraging. The trial has progressed to Phase 2, with monthly dosing of patient volunteers for six months to further assess the safety and efficacy of SerpinPC.

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CIMR researcher recognised in 2021 New Year Honours

Congratulations to Dr Mike Weekes who was awarded a British Empire Medal for services to the NHS during the COVID-19 pandemic. Dr Weekes developed a comprehensive COVID-19 screening programme for all Cambridge University Hospitals healthcare workers, and Cambridge University staff and students with symptoms of COVID-19. He simultaneously continued to lead his laboratory research at CIMR on how viruses evade intracellular defences.


Multidisciplinary funding award for CIMR early career researcher

Congratulations to Dr Jonathon Nixon-Abell (Sir Henry Wellcome Fellow at CIMR with Prof. Peter St George Hyslop FRS) and Dr Georg Krainer (Marie Skłodowska-Curie Fellow with Prof. Tuomas Knowles at the Department of Chemistry) who have jointly secured a Pump Priming Grant from the Cambridge Centre for Physical Biology. This annual funding scheme supports new collaborations between early career researchers with complementary expertise, thereby promoting multidisciplinary research in the field of physical biology in the University. Jonathan’s and Georg’s award will allow them to develop high-throughput methods of studying biomolecular condensates of protein and nucleic acid which can form inside cells – and which may have a role in neurodegenerative diseases.

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CIMR experts comment on a major advance in protein research

There has been wide interest in AlphaFold2, a program from Google’s DeepMind Artificial Intelligence (AI) network which was reported as having solved a long-standing challenge in biology. The incredible range of different behaviour and functions found across proteins depends upon their 3D structures - in turn, largely determined by protein amino acid sequences. Working out precisely how a protein chain folds from just knowing its amino acid sequence has been a major goal for decades - but now may be within reach using this AI program.

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CIMR at RAREfest2020

We’re pleased to be taking part in RAREfest2020 on Saturday 28th November. CIMR’s Prof. Stefan Marciniak and colleagues from his team Dr Jenny Dickens, Eimear Rutherford and Nikita Zubkov will be discussing their research on rare lung diseases between 12:45 – 13:30. The programme is online and registration is free, via this link: https://www.eventbrite.co.uk/e/rarefest20-virtual-science-technology-advocacy-arts-festival-tickets-82941617611

Coronavirus

Postgraduate Open Day

New publications

Rubinsztein lab 

(Nature Communications, 2021)
α-Catenin levels determine direction of YAP/TAZ response to autophagy perturbation

(Nature Chemical Biology, 2021)
VCP/p97 regulates Beclin-1-dependent autophagy initiation 

Weekes Lab (Frontiers in Cellular and Infectious Microbiology, 2021)
Rapid Degradation Pathways of Host Proteins During HCMV Infection Revealed by Quantitative Proteomics

Robinson lab (Journal of Cell Biology, 2021)
Rag GTPases and phosphatidylinositol 3-phosphate mediate recruitment of the AP-5/SPG11/SPG15 complex

Rubinsztein lab (Cell Reports, 2020)
mTORC2 Assembly Is Regulated by USP9X-Mediated Deubiquitination of RICTOR

Ron lab (eLife, 2020)
Calcium depletion challenges endoplasmic reticulum proteostasis by destabilising BiP-substrate complexes

Ron lab in collaboration with the Ito lab, RIKEN (Molecular Cell, 2020)
ISRIB blunts the Integrated Stress Response by allosterically antagonising the inhibitory effect of phosphorylated eIF2 on eIF2B

Raymond and Reid labs (American Journal of Human Genetics, 2020)
De Novo VPS4A Mutations Cause Multisystem Disease with Abnormal Neurodevelopment

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

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