Publication highlights

Dysregulation of an enzyme called peptidyl arginine deiminase IV (PADI4) has been linked to many diseases including various cancers and atherosclerosis. However, little is known about its regulation within cells, largely due to al ack of appropriate chemical tools. In this study researchers at the Crick used the RaPID system, a very powerful screening technology, to identify binders of PADI4 from DNA-encoded libraries of more than a trillion cyclic peptides. We developed these binders into three novel cyclic peptide chemical tools that modulate PADI4 activity: one to target the active conformation of PADI4, one to bind to the allosteric site and activate PADI4, and a third to use as a tool to identify different PADI4 protein binding partners that may regulate its activity. Together these peptides provide a new toolkit for the study of PADI4 in the context of health and disease.

Endogenous retroviruses (ERVs) are a specific group of viruses that altered human evolution by inserting themselves into our DNA. Often these alterations do not cause any changes in human health and disease, however in some cases they may impact the way a disease progresses by changing the way our genes function. This happens because ERVs can help to generate new versions of proteins. In this paper, the aim was to explore whether the calcium regulatory protein calbindin influenced lung cancer cells when present in the ERV-altered form (ERV-calbindin).

Lung cancer cell growth and inflammation was compared in the presence and absence of ERV-calbindin. The results indicated that ERV-calbindin aided lung cancer cell survival and tumour-promoting inflammation. On the other hand, ERV-calbindin deficient lung cancer cells grew slower, initiated the recruitment of immune cells called neutrophils and released the inflammatory marker interleukin-8. This creates an interplay between pro and anti-tumour immune reactions. Altogether the reduction in growth and increase in inflammation observed in the absence of ERV-calbindin is a phenomenon called “senescence”. These results imply that the presence of the ERV altered form of calbindin aids cancer cell growth and survival and could potentially pose as a future target for therapies.

Chromosomes are formed from chromatin, a complex of DNA and proteins. When cells die, chromatin is released into the surroundings and can cause inflammation and cytotoxicity. A process known as chromatin clearance is needed to remove extracellular chromatin and protect against severe disease. A collaboration led by Crick group leader Veni Papayannopoulos has found that in samples taken from people with the severest form of COVID-19 pneumonia, chromatin clearance was hindered in all cases, and when this process was affected the most, patients were less likely to survive.

Further analysis of the chromatin buildup showed that DNAses, a group of enzymes that help to break down chromatin, were being inhibited by another molecule, actin, which is released when cells die. Blood plasma samples taken from a second group of patients with microbial sepsis demonstrated a build-up of chromatin which correlated with high levels of actin in the blood. Using this information, the team developed a ‘proteomic profile’, a signature of protein levels and enzyme activity in the blood, that characterised the most severe and high-risk cases of infection. With further development, this signature could be used to help distinguish patients who might require additional treatment.

Using advanced bioinformatics approaches, we deciphered the global transcriptional response in the lungs of mice infected or challenged with a broad spectrum of infectious pathogens, including parasites, bacteria, viruses, fungi, or allergens; we also determined to what extent each of these responses is preserved in the blood. We demonstrated a unique global transcriptional signature for each of the different diseases in both lung and blood. The lung transcriptional signatures showed a gradation, ranging from IFN-inducible gene clusters, to those associated with granulocyte/neutrophil/IL-17 dominated genes, to responses dominated by expression of genes encoding TH2 cytokines, mast cells and B cells.

An important factor in determining the outcome of M. tuberculosis infection was identified in new research from the O’Garra lab. The team found that the cytokine type I interferon-induced neutrophil extracellular trap (NET) formation promotes bacterial growth and disease severity.