A new path to cell death

A new pathway to necrosis, a form of cell death, is described in July's Nature Chemical Biology. Necrosis is a common feature of human pathologies from stroke to neurodegeneration and unlike apoptosis -- a precisely orchestrated cellular pathway to initiate death -- was generally believed to be a passive cellular response to external damage. Junying Yuan and colleagues identify a previously unknown cellular pathway leading to necrosis, which they call necroptosis. The team demonstrate its involvement in conditions where not enough blood reaches the brain -- otherwise known as ischemic brain injury.

A growing number of studies have reported evidence for non-apoptotic cell death with some features of necrosis. However, scientists have had no tools to investigate the potential mechanisms behind these observations. To address this, Yuan and colleagues identified a chemical, necrostatin-1, which specifically inhibited this non-apoptotic cell death. They found that necrostatin-1 blocked all cases of this cell death, demonstrating the existence of a specific cellular pathway, necroptosis, leading to necrosis. They further showed that necrostatin-1 reduced ischemic brain injury in a mouse model of stroke, establishing a causal role of necroptosis in ischemic trauma-induced neuronal damage. Necrostatin-1 is a promising therapeutic lead for treating patients with brain injury following stroke.

In addition to its therapeutic potential, necrostatin-1 provides an important new chemical tool for investigating the precise molecular mechanism of necroptosis and the role of this pathway in other pathologies involving necrosis.

Flopping into dimerization

Retroviruses, including HIV, contain two molecules of RNA as their genomic information. An important step for infectivity is when the two pieces of RNA come together to form a dimer -- a special kind of polymer formed of two pieces stuck together. A paper in the July issue of Nature Chemical Biology reports that part of the region involved in dimer formation is unexpectedly floppy -- opening up new possibilities for exploring how viral infectivity is controlled.

Using a chemical approach, the authors investigated the structure of the dimerization domain. They added in a small molecule which could only react with nucleotides - individual bases of RNA - that were not tightly packed with other nucleotides. With this method, the authors were able to label parts of the dimerization domain that were unstructured. Surprisingly, the authors found that a region of the dimerization domain, which was formerly believed to adopt a stable packing interaction called a hairpin, is in fact flexible.

This new information about the RNA structure may have important implications for understanding retrovirus infectivity in vivo.

Immunology: CD22 Binding Captured

A surface protein central to immune response homo-binds to other molecules like itself, according to a paper in the July issue of Nature Chemical Biology. The authors suggest that the activity of the glycoprotein CD22 is controlled by its binding to other CD22 molecules; and this could provide an understanding of the role played by the many examples of protein glycosylation in immune response signalling. Identifying the precise nature of these interactions will be pivotal to developing new treatments for immune system disorders.

Of central importance to the immune response, B cells are responsible for pathogen recognition and antibody production. Their cell surface contains many glycoproteins, or proteins with attached carbohydrates. These carbohydrates are often critical for mediating cell-signaling interactions, but identifying the proteins that bind to them and thus control the glycoproteins' function has always been difficult.

Using a clever approach involving in situ cross-linking of proteins and carbohydrates, James C. Paulson and colleagues were able to identify the binding partners of CD22 at the cell surface. CD22 modulation is mediated by glycoprotein carbohydrates terminating in sialic acid, an unusual 9-carbon sugar. The author's approach took advantage of the cell's own biosynthetic machinery to incorporate an analog of sialic acidcontaining a photoactive group into the carbohydrates of B-cell surface glycoproteins. Photoactivation then caused proximal cross-linking to proteins that bind to sialic acid. Their analysis of the resulting CD22-cross-linked complex suggested that CD22 is modulated by CD22 homo-binding and not by other molecules previously thought to be CD22 ligands.

Future applications of this approach may provide an understanding of the role played by the many examples of protein glycosylation in immune response signaling. Identifying the precise nature of these interactions will be pivotal to developing new treatments for immune system disorders.

Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury

Alexei Degterev, Zhihong Huang, Michael Boyce, Yaqiao Li, Prakash Jagtap, Noboru Mizushima, Gregory D Cuny, Timothy J Mitchison, Michael A Moskowitz and Junying Yuan

Published online: 29 May 2005 | doi 10.1038/nchembio711

Abstract | Full text | PDF Supplementary information

RNA flexibility in the dimerization domain of a gamma retrovirus

Christopher S Badorrek and Kevin M Weeks

Published online: 5 June 2005 | doi 10.1038/nchembio712

Abstract | Full text | PDF | Supplementary information

Homomultimeric complexes of CD22 in B cells revealed by protein-glycan cross-linking

Christopher S Badorrek and Kevin M Weeks

Published online: 12 June 2005 | doi 10.1038/nchembio713

Abstract | Full text | PDF | Supplementary information