Publication highlights

Researchers at the Crick have discovered that Mtb, the bacterium causing tuberculosis (TB), alters its outermost layer, its lipid cell envelope, when it encounters low phosphate conditions. This allows it to survive inside human immune cells, where phosphate is restricted. It can scavenge phosphate from human lipids (fats), which are present in the lungs, allowing the bacteria to grow when no other source of phosphate is present. These findings demonstrate a method that Mtb employs to overcome the human host’s attempts to restrict its growth. The replacement lipids produced
when phosphate is restricted therefore represent new drug targets for the treatment of TB. Additionally, vaccines that target TB via its lipids should take into account the particular lipids present when the cell is phosphate starved, as demonstrated here.

Natural ion channels of biology allow cells to communicate, transfer nerve impulses, trigger sensations, and cellular processes. Biology has a variety of highly effective channels, but creating new, orthogonal systems is challenging. Researchers at the Crick have designed a system able to span a lipid bilayer, with a single internal channel, which allows the passage of certain anions and cations. They can control its activity using three biorthogonal handles - light, pH, and presence of a 'guest' molecule, which blocks the channel. This allows them to formulate a molecular logic gate, achieving a simple analogy of the complex functions of biological transmembrane proteins.

The Salmonella protein SteE forcibly reprogrammes the eukaryotic kinase GSK3 so it acts on a new set of substrates that benefit Salmonella virulence. Kinase reprogramming depends on several short linear motifs in SteE that trick GSK3 into recognising SteE as a 'normal' cellular signalling partner. Researchers at the Crick have shown how each motif contributes to manipulating GSK3, and revealed the existence of SteE-like proteins in other bacterial pathogens. This work will aid the rational design of synthetic reprogramming proteins.

Researchers have shown that the transfer of genes from bacteria into more complex organisms can give them an advantage but requires remodelling of the host’s biology. The lab explored the integration of a horizontally transferred gene coding for an enzyme called squalene-hopene cyclase (Shc1) from bacteria into S. japonicus yeast. They found that S. japonicus switches between using an enzyme that generates sterols in the presence of oxygen, Erg1, and the horizontally acquired Shc1 enzyme to produce hopanoids in conditions without oxygen. They showed that hopanoids are best accommodated in the membrane if it is made of asymmetrical lipids, so S. japonicus has adapted to produce two different lengths of fatty acids. The researchers concluded that the bacterial gene provided S. japonicus with an advantage against other yeast species, especially in high temperature and low oxygen environments.

Researchers at the Francis Crick Institute, King’s College London and the University of Fribourg have developed polymer water channels, similar to commonly used plastics, that can draw salt out of water, inspired by the body’s own water filtering system. If their innovation could be scaled up and produced industrially, this could help to filter seawater to create drinking water. The new channels mimicked aquaporins, proteins that rapidly transport water across cell membranes while excluding salt, and were organised into a helix structure called polymers or into cyclic structures called macrocycles. The pores inside the two types of channels were filled with a chemical mixture of fluorine and molecules called hydrocarbons, which together create a greasy layer. Through a series of experiments, the team confirmed that the channels actively transported water across a membrane and excluded salt.

DNA in our cells must be copied only once in the life cycle of a cell to maintain gene copy number and prevent genome instability. To make sure that this happens, loading of the enzyme (MCM), which separates two strands of the double helix, is separated in time from its activation. Once activated, MCM uses the energy derived from ATP hydrolysis to move along one DNA strand and physically separate the other strand, achieving DNA unwinding. Before activation, MCM is recruited by a loader onto the double helix. Researchers knew that, to complete loading, ATP hydrolysis by MCM is required but did not know why. Here researchers at the Crick show that MCM uses ATP hydrolysis to move along duplex DNA away from its loader. Their study also provides new mechanistic information about how polymer translocases (like DNA motors or the proteasome) use ATP hydrolysis to drive movement.

The germinal centres (GCs) of the body act as factories where antibody-secreting B cells are fine-tuned to reach their highest antigen affinity. GC-B cells cycle between two GC zones, undergoing antigen-driven selection and initiating cell division in the light zone (LZ), before migrating to the dark zone (DZ), where they vigorously proliferate. Initiation of cell division in the LZ was a puzzle, as the low-oxygen conditions in the LZ normally induce cell cycle arrest. Researchers at the Crick showed that a microRNA called miR-155 metabolically reprogrammes LZ GC-B cells by regulating genes that enhance energy production and prevent cell death. This process is essential for effective immune function in the face of infection.

The MCM helicase enzyme separates the two strands of the double helix, enabling DNA replication, with two copies of MCM (a “double hexamer”) marking where replication can start. We have a clear understanding of how double hexamers are loaded in yeast, but not in human cells. Researchers from the Crick reconstituted double hexamer loading with purified human proteins and determined the atomic structures. They found that, unlike in yeast, loading of a human double hexamer is sufficient to start opening DNA. Two alternate loading pathways exist to load human double hexamers. Loading factors that are essential in yeast only play a dispensable, regulatory role in the human system. Thus, while the double-hexamer loaders are conserved throughout evolution, how they function is different. This work begins to unravel how human cells regulate initiation of DNA replication, ensure that their genome is duplicated only once, and prevent chromosome instability and cancer.