Publication highlights

When normal cells become cancer cells, they undergo a series of genetic changes that allow them to divide indefinitely. One such change involves the loss of a protein called Schlafen 11 (SLFN11), which occurs in half of all cancers. SLFN11 activity results in programmed cell death in response to damaged DNA, which naturally occurs during cancer cell transformation. Thus, loss of SLFN11 renders cancer cells immune to DNA damage and resistant to wide range of chemotherapies currently used in the clinic. However, how damaged DNA activates SLFN11 to cause programmed cell death is not known. Here, researchers at the Crick have uncovered what cellular processes lead to a specific type of DNA damage that activates SLFN11 and programmed cell death. This work provides insight as to why half of all cancers lose SLFN11 in response to naturally occurring DNA damage.

Type 2 immunity is central to parasite protection but when dysregulated causes allergy and atopy (tendency to produce an immune response to allergens), and influences neuroprotection, ageing and cancer. Researchers at the Crick have discovered two new ways the receptor for the type 2 cytokines IL-4 and IL-13 (called IL-13Ra1) is modulated. One is sex-specific – female hormones repress expression of this common receptor so that female cells are less responsive. The other is through an ancient retrovirus that integrated near the IL-13Ra1 gene of our primate ancestors, which produces a partially defective IL-13Ra1 that can block the traditional version from signalling. This is a fascinating example where an ancient retroviral infection has affected modern human immunity.

Toxoplasma is a single-cell parasite that infects any warm-blooded animal. It can persist for a long time in the host as it can withstand pathogen-clearing mechanisms. How the parasite circumvents clearance in a wide host range, with different immune mechanisms, remains unknown. To prevent being killed, the parasite secretes ~250 proteins into the host cell. Which of these effector proteins enable infection of all species, and in parasite strains that are particularly virulent in humans, has not been established. Researchers at the Crick and GIMM identified a core set of proteins required for survival in different mouse species with varying susceptibility to Toxoplasma infection. Deletion of the top hit, a protein called GRA12, led to increased host-cell death and early exit of the parasite from the infected cell. The team propose that instead of one virulence factor required across all species, the parasite evolved a suite of effector proteins to counter unique clearance mechanisms in different hosts.

The modification of proteins with a small regulatory protein called ubiquitin influences the majority of cellular functions and malfunction is implicated in many diseases. To capitalise on the therapeutic potential of regulating ubiquitination processes, we need to understand the mechanisms of the enzymes that catalyse it: E3 ubiquitin ligases. Researchers at the Crick characterise a previously unrecognised sub-family of ‘pseudoligases’, which lack key structural and catalytic features. These deviations mean that they cannot catalyse ubiquitination but instead appear to regulate active E3 ligases. Uncovering this unexpected evolutionary strategy takes us a step closer to understanding and manipulating the ubiquitin system.

Researchers at the Crick previously discovered that the tail of Influenza virus M2 (matrix 2) protein binds directly to the autophagy (self-eating) protein LC3, which becomes attached to membranes following collapse of pH gradients during infection. In this paper, the team describes a crystal structure of the M2 tail bound to LC3, and report that an unstructured region directly upstream of the interaction is a caspase cleavage motif. Caspases are proteases which can cleave cellular proteins during cell death. In this case, the paper shows that caspase cleavage of M2 disrupts the interaction between M2 and LC3. Functionally, this affects M2 transport to the plasma membrane for virion budding, also disrupts influenza from forming long filaments at the cell surface. This is speculated to be a mechanism to change the structure of virions during cell death, to one that does not require as many cellular resources.

Small molecule probes offer powerful tools for the study of biological systems and can serve as starting points for the development of therapeutics. The vast majority of human proteins lack such chemical tools, which hinders our ability to explore their function in the context of health and disease. Screening libraries of “reactive fragments”, small molecules that form covalent bonds with their protein targets, by mass spectrometry enables the discovery of new ligands in the native cellular environment. Together with GSK as part of the Crick-GSK Biomedical LinkLabs Prosperity Partnership, researchers at the Crick have developed a robust and versatile proteomics platform for profiling of cysteine-reactive fragments against the native proteome and have identified hundreds of new protein-ligand interactions for probe development.

Researchers at the Francis Crick Institute and UCL, funded by Cancer Research UK, have unveiled the first computer algorithm capable of identifying which cell populations within a tumour drive aggressive growth. The innovative algorithm, called SPRINTER, analyses individual cells within a tumour to identify those that are growing the most rapidly. The algorithm was used to analyse nearly 15,000 cancer cells from a patient with non-small cell lung cancer (in TRACERx and PEACE studies). SPRINTER revealed that the cells that were growing the fastest were responsible for spreading the cancer to other parts of the body, even from other metasasised tumours. It also showed that these cells shed more of their DNA into the bloodstream. The possibility of detecting aggressive cancer cell populations early and monitoring them over time offers a new avenue for more proactive and personalised cancer care.