Researchers at the Crick are tackling the big questions about human health and disease, and new findings are published every week. Our faculty have picked some of the most significant papers published by Crick scientists, all of which are freely available thanks to our open science policy.
CD1d-mediated lipid presentation by CD11c+ cells regulates intestinal homeostasis
Intestinal homeostasis requires a continuous dialogue between commensal bacteria and intestinal immune cells. Natural Killer T (NKT) cells are a population of CD1d-restricted lipid-reactive lymphocytes contributing to the regulation of mucosal immunity, but the mechanisms underlying this are poorly understood. Here we show that lipid presentation by CD1d+ intestinal dendritic cells and macrophages controls NKT cell function and activation which in turn regulates commensal bacteria and immune cell populations in the gut. These results reveal an NKT cell-dendritic cell crosstalk as a key mechanism for the regulation of intestinal homeostasis.
A protease cascade regulates release of the human malaria parasite Plasmodium falciparum from host red blood cells
This study showed that egress involves an enzyme cascade in which the serine protease SUB1 activates a second, cysteine protease called SERA6, enabling SERA6 to rapidly and precisely cleave the major red cell cytoskeletal protein β-spectrin and dismantle the cytoskeleton. It provides the first plausible model to explain how the parasite accomplishes timely rupture of its host cell membrane.
Stabilization of reversed replication forks by telomerase drives telomere catastrophe
This study defined the mechanism leading to critically short telomeres in the absence of RTEL1 and showed that telomerase, which extends telomeres in normal cells, is pathological when forks encounter an obstacle within the telomere. We showed that replication forks stall and reverse at persistent t-loops, which creates a pseudo-telomere substrate that is inappropriately stabilised by telomerase. Removing telomerase or blocking replication fork reversal rescued telomere dysfunction in Rtel1 deficient cells. We proposed that when persistent t-loops stall the replisome, telomerase inhibits fork restart, triggering the excision of the t-loop by SLX1/4 and loss of a substantial part of the telomere.
Nervous system regionalization entails axial allocation before neural differentiation
The prevailing view of neural induction in vertebrate embryos had been that cells are initially induced with anterior (forebrain) identity and then caudalising signals convert a proportion to posterior fates (spinal cord). Using chromatin accessibility, to define how cells adopt region-specific neural fates, combined with genetic and biochemical perturbations, we found that contrary to the established model, cells commit to a regional identity before acquiring neural identity. These findings prompt a revision to textbook models of neural induction. The study illustrates our adoption of new genomic methods (ATACseq) to address long-standing questions, and our capacity to productively collaborate with computational biologists.
Phosphopeptide binding by Sld3 links Dbf4-dependent kinase to MCM replicative helicase activation
Here we showed that Sld3, which we previously identified as being one of two essential cyclin dependent kinase (CDK) substrates in replication, is a phosphopeptide binding protein which binds specifically to Mcm4 and Mcm6 when they have been phosphorylated by Dbf4 dependent kinase (DDK). Sld3 then directly recruits Cdc45 to MCM and, via CDK phosphorylation, recruits the remaining firing factors. We had previously shown that Sld3 is also one of two targets of the DNA damage checkpoint kinase involved in inhibiting origin firing in response to DNA damage. Thus, Sld3 plays key roles with all three kinases that regulate replication (CDK, DDK, Rad53).
The mechanism of eukaryotic CMG helicase activation
This paper provided the first view of how the inactive MCM double hexamer is converted to two active CMG helicases. We showed MCM remains bound to ADP after loading; firing factors trigger ADP-ATP exchange; ATP rebinding causes double hexamer splitting, initial DNA melting and CMG formation. Active helicases then translocate N-terminus first.
α-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson’s disease
Protein aggregation drives neuronal death in Parkinson’s disease, although how transition of monomeric protein structures to aggregated forms causes toxicity is unknown. We demonstrate that aggregation of the protein α-synuclein generates beta sheet-rich oligomers, which localise to the mitochondrial inner membrane, where they impair complex I-dependent respiration, induce oxidation of ATP synthase and cause mitochondrial lipid peroxidation. These oxidation events result in opening of the permeability transition pore, triggering mitochondrial swelling, and ultimately cell death. This work highlights how structural conversion of a protein changes its physiological interaction with proteins and lipids, and induces pathology in human cell models of disease.
Early-life exposure to low-dose oxidants can increase longevity via microbiome remodelling in Drosophila
This reports the first identification, in any species, of the microbiome as a key mediator of developmental stress-induced longevity. We found that mild oxidative stress during development robustly increases lifespan via the selective elimination of Acetobacter from the microbiome. This study also highlights that targeted remodelling of the early-life microbiome can provide an efficient strategy for extending healthspan and lifespan.
Return to quiescence of mouse neural stem cells by degradation of a proactivation protein
This paper provided the first evidence that stem cells in the adult mouse hippocampus are heterogeneous in their behaviour, with most stem cells differentiating and leaving the niche after they have become active but a small fraction returning to a shallow state of quiescence. These “resting cells” have an essential role in the long-term maintenance of an active stem cell pool.
Epithelia use butyrophilin-like molecules to shape organ-specific γδ T cell compartments
This paper established that intestinal epithelial cells use BTNL/Btnl molecules to select for and regulate tissue-specific gamma delta T cell compartments. It established a biological mechanism by which epithelial cells communicate with local T cells at steady-state (“normality sensing”). Following on from our prototypic discovery of such a mechanism in mouse skin, the work established conservation of the process across tissues as well as across species. The system is unperturbed by microbial colonisation.
Long-range signaling activation and local inhibition separate the mesoderm and endoderm lineages
The induction of endoderm and mesoderm by the signalling molecule Nodal has long been a textbook example of how a morphogen patterns vertebrate tissues. This study overturned the view that tissues are patterned through a single long-range morphogen gradient. Instead we demonstrated that Nodal functions in an incoherent feedforward loop with Fgf, to determine endoderm and mesoderm specification. Nodal induces long-range Fgf signaling, which is required for mesoderm induction, while simultaneously inducing a cell-autonomous Fgf signaling inhibitor within cells destined to become endoderm. This work represents a major step forward in deciphering the organising principles underlying early embryonic patterning.
Plasmodium-specific atypical memory B cells are short-lived activated B cells
This paper provides strong evidence that “atypical” B cells are short-lived activated B cells, and are probably the result of chronic stimulation and not the cause of chronic malaria. This questions the commonly held view that atypical B cells are evidence of an aberrant or defective response in malaria.
Sex reversal following deletion of a single distal enhancer of Sox9
This systematic study revealed the complexity of the Sox9 regulatory region, but just one enhancer, “Enh13”, was shown by mutation studies to be essential for testis and subsequent male development. Sox9 expression is at the same very low level in XY Enh13 mutant embryos as in control XX gonads. Enh13 is efficiently bound by Sry in vivo and functions to initiate Sertoli cell fate during a short time window. This is in contrast to other redundant enhancers (e.g. TES) that bind Sry, but act later. This study helped explain Disorders of Sex Differentiation (DSDs), due to deletions and duplications mapping far upstream of Sox9, where the human Enh13 equivalent is located, as well as showing that some enhancers can be pioneering rather than redundant.
CDK substrate phosphorylation and ordering the cell cycle
A phosphoproteomics analysis of CDK substrates has shown that the correct cell cycle temporal order of CDK substrate phosphorylation can be established by a single CDK. It is shown that there is a 50-fold increase of in vivo CDK activity during the cell cycle. Temporal order is achieved by a combination of this rise with differential sensitivity of substrates to CDK activity. Phosphosite turnover is very rapid which helps ensure sharp cell cycle transitions.
Quantitative phosphoproteomics reveals the signaling dynamics of cell-cycle kinases in the fission yeast Schizosaccharomyces pombe
A phosphoproteomics analysis of cell cycle protein kinases indicates that different mitotic kinases (CDK, NIMA related, Polo-like and Aurora) are activated sequentially during mitosis. The timing of these waves of activation is determined by the differential sensitivities of the mitotic kinases to the rising level of upstream CDK activity.
Neutrophil extracellular traps in immunity and disease
The priming signals in sterile chronic inflammatory diseases remained elusive. Moreover, NETs were mostly thought to serve as an antimicrobial defence mechanism. This work showed that NETs are proinflammatory and provide the priming signals for inflammation in atherosclerosis. It has important implications for our understanding of the mechanisms driving many inflammatory conditions and the important amplification mechanisms involving neutrophil-macrophage crosstalk.
Inhibitor-induced HER2-HER3 heterodimerisation promotes proliferation through a novel dimer interface
The paper was a broad collaboration with a team from one of our Partner Institutions and others, and illustrates how our learning from insights in the PKC field, here concerning kinase nucleotide pocket occupation, can impact our understanding of the broader kinome. Specifically the work demonstrates that the pseudokinase HER3 which is upregulated in cancer and drug resistance settings, undergoes essential nucleotide pocket occupation dependent changes in conformation to drive HER2 partner dependent signalling. Of importance clinically, the paper offers a route to small molecule-based intervention and also raises questions of inhibitor liability associated with HER3.
Intron retention and nuclear loss of SFPQ are molecular hallmarks of ALS
We demonstrated aberrant intron retention in ALS-causing mutations. This is the first description of abnormal intron retention in ALS. The most significantly retained intron in is the SFPQ transcript, which 'drags' SFPQ protein out of the nucleus. SFPQ nuclear loss is a new universal molecular hallmark of ALS across iPSC, mouse models and in sporadic ALS post-mortem tissue.
NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control
In this paper we showed that cDC1 recruitment and infiltration in several mouse tumour models depends on the chemokines CCL5 and XCL1 produced by NK cells. In human cancers, CCL5/XCL chemokine transcripts correlate with gene signatures for NK cells and cDC1 and predict overall survival in melanoma, head and neck cancer, breast cancer and lung adenocarcinoma. Therefore, our data uncovered a mechanism for cDC1 recruitment into tumours that is translatable to humans and cancer patient survival.
The linker histone H1.0 generates epigenetic and functional intratumor heterogeneity
This study showed that epigenetic mechanisms play an important role in generating functional heterogeneity within tumours, and can override genetic alterations that initiate the disease by inhibiting cell proliferative potential during tumour growth. The finding that heterogeneous patterns of H1.0 are broadly observed in cancer and that H1.0 is an independent predictor of patient survival in multiple types of solid tumours makes a strong case for a general role of epigenetic regulators in cancer. Mechanistic characterisation of how H1.0 controls malignant self-renewing states also provided insights into general mechanisms through which the linker histone regulates gene expression.