Publication highlights

Children born with mutations in the ARPC5 protein, which is part of the internal cytoskeleton, experience immunodeficiency and a high risk of sepsis. Researchers at the Crick investigated immune system function in mice with and without ARPC5 mutations, observing inflammation in adult mice with ARPC5 deficiency that mirrored that in humans. They showed that this was due to a big change in bacterial composition in the gut after weaning, triggering intestinal inflammation, as giving antibiotics to ARPC5-deficient mice at a critical four-week time point fully prevented the disease from developing. Finally, the team showed that macrophages with ARPC5 mutations had lost their usual shape and could no longer kill bacteria effectively, leading to an overwhelming response to the microbiome.

The Arp2/3 complex initiates the growth of new actin filaments from the side of pre-existing filaments to generate branched actin networks that are essential for many different cellular processes. However, it can also nucleate single linear actin filaments when activated by WISH/DIP/SPIN90 family proteins. Unexpectedly, researchers at the Crick together with collaborators at Birkbeck, found Arp2/3 can nucleate bidirectional linear actin filaments when activated by SPIN90. By determining the structure of SPIN90 bound to actin filaments, they uncovered the mechanism by which this bidirectional nucleation occurs. Their analysis demonstrates that single filament nucleation by Arp2/3 is mechanistically more like branch formation than previously appreciated.

Researchers have uncovered that topoisomerase 2, which maintains the integrity of our genome, also plays critical roles in vaccinia virus replication. Upon infection, viral protein synthesis triggers the relocation of both topoisomerase 2 isoforms, TOP2A/B, from the nucleus to the cytoplasm, where they carry out opposing functions. TOP2A promotes replication by interacting with viral DNA replication machinery, whereas TOP2B suppresses infection by enhancing the formation of double-stranded RNA and antiviral granules. This study provides new insights into host-poxvirus interactions and highlights important roles for topoisomerase 2 outside the nucleus. It also suggests that topoisomerase inhibitors used in the clinic would make excellent antiviral drugs.

The shape, function, and movement of cells in our body depends on a branched skeleton made of actin filaments. This dynamic skeleton is stabilized by cortactin, a protein that is known to promote the spread of cancer. Researchers from Birkbeck College and the Crick have now determined how cortactin stabilizes actin branches by determining its structure using cryo-electron microscopy. The structure which overturns previous models has provided important new molecular insights into how cortactin binds actin branches and will help in the design of drugs/inhibitors that inhibit its function.