Bishop et al. Hyphal growth in Candida albicans requires the phosphorylation of Sec2 by the Cdc28/Ccn1/Hgc1 kinase. EMBO J 2010 29 2930-2942

The fungal pathogen Candida albicans lives in the human gut, mouth and genital tract, and infects about 80% of the population with no harmful effects. Most women at some point experience overgrowth in the genital tract, which is known as thrush. Candida is (after MRSA) the second most common cause of death from hospital-acquired infections, because it thrives in immunocompromised patients, for example after transplants or chemotherapy, or in AIDS patients. In these cases, it changes from its resting state of round yeast-like cells by pushing out long fungal hyphae, which can push their way into the bloodstream (see Figure). It is therefore the hyphae which produce the dangerous infections.

This work by Prof. Sudbery’s group looks at how hyphae grow. It shows that they use an enzyme that is well known in baker’s yeast, where it controls budding of secretory vesicles, used to export chemicals out of the cell. Thus, the work suggests that Candida has adapted an existing system for moving chemicals around the cell, and turned it into a mechanism for extending the growing tip of hyphae. This means that we can use our existing understanding of baker’s yeast to help understand hyphal growth in Candida, and ultimately to treat Candida infections.

This builds on work published by Prof Sudbery in 2009 in Nature 459 657 on pathogenic genes in the Candida genome.

Turner et al. Peptidoglycan architecture can specify division planes in Staphylococcus aureus. Nature Communications 2010 1, 26.

Staphylococcus aureus is responsible for a large number of diseases, including food poisoning, staph infections, and the well-known ‘superbug’ MRSA hospital infections. It is a spherical bacterium, which grows by getting bigger until it reaches a predetermined limit, at which point it splits into two, by building a septum across the middle of the cell. Remarkably, when S. aureus divides into two, it always splits in a direction at right angles to the direction used in the two previous divisions: in other words, it splits sequentially along x, y and z planes (see Figure: in order, white, red and pink, then white again). This paper shows how S. aureus ‘knows’ which direction to split. This is an important question, because most antibacterials, including drugs directed against S. aureus such as penicillin and vancomycin, act by weakening the bacterial cell wall, because this is a structure unique to bacteria. So understanding how the cell wall grows naturally is likely to be an important key in developing new drugs against S. aureus.

This work by Prof Foster’s group explains how orthogonal cell division occurs. At each cell division, a thick layer of cell wall is formed across the middle of the cell. At the outside of the cell this is visible as a ‘piecrust’ (central part of figure). After the cell has split into two, each half then has one hemisphere with remnants of piecrust from previous divisions, and one undecorated hemisphere. The next division will be along the red ‘quarter rib’, which is the least complete part of old piecrust.

Long et al. Dimerisation of the UBA domain of p62 inhibits ubiquitin binding and regulates NF-κB signalling. J Mol Biol 2010 396 178

Paget’s disease of bone is a chronic disease that affects up to 8% of the population and leads to enlarged and deformed bones, with chronic pain. It arises from a defect in a signalling pathway in osteoclasts, the specialist cells that remove old bone tissue and lead to remodelling of bone. A common cause of the disease is a mutation in a protein called p62, and in particular in part of the protein called the UBA domain, which binds to ubiquitin. Ubiquitin is a tag that signals protein degradation and was the subject of the Nobel Prize in Chemisty in 2004: chains of ubiquitin get attached to proteins that are marked for degradation. It has however been unknown how mutations in UBA affect the function of p62.

This work by Prof Williamson’s group shows that the mechanism is remarkably simple. Monomeric UBA binds to ubiquitin and thereby turns on a signal. However, UBA easily forms dimers, which do not bind ubiquitin and are thus inactive because the same part of the protein surface is used for dimerisation and ubiquitin binding (part (a) of figure). Ubiquitin affinity can therefore be regulated by factors affecting protein dimerisation.

This is particularly interesting because it means that p62 will bind to ubiquitin chains but not monomers (part (b)). This work provides a novel approach to drugs against this debilitating disease: instead of targeting ubiquitin binding, we can target p62 dimerisation, which should be much more specific.