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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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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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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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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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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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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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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.

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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

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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 (http://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 (http://tinyurl.com/y9vm8feq). As a result, there is no reason to suspect that the virus attacks haemoglobin.

Professor Michael Wakelam 1955-2023

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.

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A range of different research expertise is needed in the global response to the ongoing 2023-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, 2023-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. 2023-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 2023-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

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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 2023.

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.

2023 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.

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Latest guidance

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New publications

Weekes lab (PNAS, 2023)
Human cytomegalovirus protein pUL36: A dual cell death pathway inhibitor

Woods lab (Cell Reports, 2023)
Human Labor Pain Is Influenced by the Voltage-Gated Potassium Channel KV6.4 Subunit

Deane lab (Nature Communications, 2023)
The receptor PTPRU is a redox sensitive pseudophosphatase

Rubinsztein lab (Nature Communications, 2023)
Leucine regulates autophagy via acetylation of the mTORC1 component raptor

Rubinsztein lab in collaboration with the Goldberg lab, Harvard (PNAS, 2023)
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Griffiths lab (eLife, 2023)
Stimulation strength controls the rate of initiation but not the molecular organization of TCR-induced signalling

Buss lab (Journal of Cell Science, 2023)
OPTN recruitment to a Golgi-proximal compartment regulates immune signalling and cytokine secretion

Rubinsztein lab (Developmental Cell, 2023)
A DNM2 Centronuclear Myopathy Mutation Reveals a Link between Recycling Endosome Scission and Autophagy

Buss lab (Biology of Reproduction, 2023)
Myosin VI maintains the actin-dependent organization of the tubulobulbar complexes required for endocytosis during mouse spermiogenesis

Weekes lab (Scientific Reports, 2023)
Comprehensive cell surface proteomics defines markers of classical, intermediate and non-classical monocytes

Buss lab (Traffic, 2023)
Ultrastructural insights into pathogen clearance by autophagy

Read lab (Acta Crystallographica Section D, 2023)
Measuring and Using Information Gained by Observing Diffraction Data

Read lab (Acta Crystallographica Section D, 2023)
Factors influencing estimates of coordinate error for molecular replacement

Ron lab (eLife, 2023)
Unstructured regions in IRE1α specify BiP-mediated destabilisation of the luminal domain dimer and repression of the UPR

Weekes lab (eLife, 2023)
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Rubinsztein lab (eLife, 2023)
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Ron lab (eLife, 2023)
The ribosomal P-stalk couples amino acid starvation to GCN2 activation in mammalian cells

Griffiths lab (Journal of Clinical Investigation, 2023)
Loss of ARPC1B impairs cytotoxic T lymphocyte maintenance and cytolytic activity

Reid lab (Frontiers in Neuroscience, 2023)
Spastin MIT Domain Disease-Associated Mutations Disrupt Lysosomal Function

Deane lab (Wellcome Open Research, 2023)
The lipid transfer protein Saposin B does not directly bind CD1d for lipid antigen loading

Reid lab (Cellular and Molecular Life Sciences, 2023)
ESCRT‑III‑associated proteins and spastin inhibit protrudin‑dependent polarised membrane traffic

Ron lab (EMBO Journal, 2023)
An oligomeric state‐dependent switch in the ER enzyme FICD regulates AMPylation and deAMPylation of BiP

Robinson lab (Traffic, 2023)
Fast and cloning‐free CRISPR/Cas9‐mediated genomic editing in mammalian cells

Weekes lab (Communications Biology, 2023)
Quantitative comparative analysis of human erythrocyte surface proteins between individuals from two genetically distinct populations

St George-Hyslop lab (Cell, 2023)
RNA Granules Hitchhike on Lysosomes for Long-Distance Transport, Using Annexin A11 as a Molecular Tether

Siniossoglou lab (Developmental Cell, 2023)
Compartmentalized Synthesis of Triacylglycerol at the Inner Nuclear Membrane Regulates Nuclear Organization

Weekes lab (Cell Metabolism, 2023)
Epstein-Barr-Virus-Induced One-Carbon Metabolism Drives B Cell Transformation

Warren lab (Blood, 2023)
EFL1 mutations impair eIF6 release to cause Shwachman-Diamond syndrome.

Warren lab (eLife, 2023)
Mechanism of completion of peptidyltransferase centre assembly in eukaryotes

Weekes lab (Cell Reports, 2023)
Quantitative Temporal Proteomic Analysis of Vaccinia Virus Infection Reveals Regulation of Histone Deacetylases by an Interferon Antagonist

Rubinsztein lab (Nature Communications, 2023)
Felodipine ameliorates neurodegeneration in mice

Sharpe lab (eLife, 2023)
The receptor PTPRK selectively dephosphorylates junctional regulators

Ron lab (Nature Comm, 2023)
MANF anatagonizes nucleotide exchange by the enodplasmic reticulum chaperone BiP

Seminars

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Research Advance

Research Advance

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New Wellcome Trust Fellowship award at CIMR

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New Wellcome Trust Fellowship award at CIMR

Published commentary on haemoglobin and COVID-19.

Professor Michael Wakelam 1955-2023

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New Wellcome Trust Fellowship award for CIMR early-career researcher

Medal Lecture from CIMR Principal Investigator

Meeting prize for CIMR PhD Student

2023 CIMR Research Retreat

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平行加速器安卓下载

Research Advance

Research Advance

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New Wellcome Trust Fellowship award at CIMR

平行加速器安卓下载

New Wellcome Trust Fellowship award at CIMR

Published commentary on haemoglobin and COVID-19.

Professor Michael Wakelam 1955-2023

平行加速器app下载

New Wellcome Trust Fellowship award for CIMR early-career researcher

Medal Lecture from CIMR Principal Investigator

Meeting prize for CIMR PhD Student

2023 CIMR Research Retreat

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Seminars

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Study at Cambridge

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Research at Cambridge