Research highlights

Binding NEMO

Tumor necrosis factor (TNF) induces activation of transcription factor NF-κB, leading to upregulation of prosurvival and inflammatory responses. In Molecular Cell, Chen and colleagues demonstrate the recognition process by which the NF-κB-activating kinase IKK is recruited to TNF receptors in response to TNF. Polyubiquitinylation of the receptor-proximal kinase RIP1 is required for recruitment of the kinase TAK1 and NEMO, the regulatory component of the IKK complex, to activated TNF receptors. NEMO specifically recognizes K63-polyubiquitinated RIP1. Substitution of RIP1 at L377 abolishes NEMO recognition and IKK activation and prevents 'downstream' NF-κB-dependent responses. The polyubiquitin-binding domain of NEMO maps to a conserved leucine zipper thought to mediate coiled-coil protein interactions; alteration of several key hydrophobic residues in this domain inhibits both binding of NEMO to RIP1 and IKK activation. Thus, TNF-dependent RIP1 polyubiquitinylation provides a necessary scaffold for recruitment of NEMO in the proximity of the 'upstream' activating kinase TAK1, resulting in IKK and NF-κB activation. LAD

Mol. Cell 22, 245–257 (2006)

Pairing regulations

Self-assembly of immune receptor complexes requires transmembrane charged residues, but whether, like several nonimmune receptor complexes, self-assembly is also influenced by extended nonpolar motifs is not known. In PLoS Biology, Wucherpfennig and colleagues present mutagenesis data demonstrating that immune receptor assembly proceeds regardless of the identity of the hydrophobic transmembrane residues. The specificity of interactions between signaling subunits and immune receptors (NKG2D associates with DAP10 but not CD3δε; TCRα associates with CD3δε but not DAP10) is determined by the identity as well as the location of charged transmembrane residues, by steric hindrance between extramembranous domains and by competition for limiting signaling subunits. These results shed light on the mechanism by which specific pairing of immune receptors and signaling subunits is ensured. The immune consequences of inappropriate associations between costimulatory receptors and stimulatory signaling subunits could be disastrous. CB

PLoS Biol. (25 April 2006) doi:10.1371/journal.pbio0040142

Dynamic spreading

Activation of lymphocyte antigen receptors occurs at 'synapses' with antigen-presenting cells (APCs). In Science, Fleire et al. find that B cells engage APCs in a two-phase response in which initial high-affinity contacts between surface immunoglobulin and membrane-bound antigen leads to 'spreading' of the B cells over the surface of the APC. The area of spreading is proportional to the affinity of the B cell receptor to the antigen, over a range of 1–2 logs. Spreading occurs rapidly, within 2–4 minutes, after which the B cell 'gathers' the antigen to a central cluster by contraction. This two-phase antigen 'collection' process, which requires B cell receptor signaling and actin polymerization, enables B cells to acquire antigens for processing and presentation to lymphocytes. Moreover, the wide range of antigen affinities over which collection occurs may help to explain the wide discriminatory ability of B cells. DCB

Science 312, 738–741 (2006)

Curbing T _H 1 inflammation

In vitro studies indicate that interleukin 25 (IL-25) is produced by T helper type 2 (T_H2) cells and amplifies T_H2 responses. In the Journal of Experimental Medicine, Artis and colleagues analyze IL-25 function in vivo. Il25^−/− mice fail to generate T_H2 responses needed to fight off Trichuris muris parasites. Treatment with anti-IL-12 and antibody to interferon-γ restores T_H2 responses in Il25^−/− mice, indicating that IL-25 promotes T_H2 responses at least in part by suppressing T_H1 responses. Mouse strains susceptible to T. muris develop chronic infections but show little gut inflammation. In contrast, Il25^−/− mice, which also fail to eradicate T. muris, develop gut inflammation characterized by increased IL-17 and interferon-γ but normal amounts of IL-10 in the gut and draining lymph nodes. The mechanism by which IL-25 limits T_H1 inflammation remains to be identified. Nevertheless, these data emphasize IL-25 as a potential target for therapies aimed at dampening pathological T_H1 responses. CB

J. Exp. Med. 203, 843–849 (2006)

Helicase specificity

RIG-I and Mda5 are cytoplasmic helicases that act as sensors for double-stranded RNA and RNA viruses. In Nature, Kato et al. demonstrate that RIG-I and Mda5 have different specificities for RNA ligands. Mice deficient in Mda5 but not those deficient in RIG-I fail to produce interferon-α/β in response to poly(I)·poly(C). Embryonic fibroblasts from these 'knockout' mice further distinguish the responses of the helicases, as RIG-I is essential for the interferon response to in vitro–transcribed double-stranded RNA, paramyxoviruses, influenza virus and Japanese encephalitis RNA viruses, whereas Mda5 is required for picornaviruses only. Virus infection of RIG-I- and Mda5-deficient mice demonstrates that the helicase-virus specificity extends to an in vivo setting. Thus, RIG-I and Mda5 helicases are differentially required for host defense against RNA viruses. DCB

Nature (6 April 2006) doi:10.1038/nature04734

Sis silencing

Immunoglobulin gene rearrangement is regulated by allelic exclusion, but how this occurs is unknown. In Immunity, Liu et al. show the recombination-silencing element Sis acts to repress Igk accessibility and rearrangement. Sis is a regulatory site located between joining (J_κ) and upstream variable (V_κ) gene segments. V_κ-to-J_κ recombination, mediated by recombination-activating gene products, deletes Sis from the germline sequence. Sis contains multiple recognition sites for the transcriptional repressor Ikaros, which when bound to Sis correlates with nuclear heterochromatin localization. Loss of Sis does not affect the tissue or temporal specificity of Igk recombination, but higher frequencies of recombination occur on the targeted allele in bone marrow pre–B cells. Loss of Sis also leads to reduced recruitment of Igk to centromeric heterochromatin regions associated with silent genes. These data suggest Sis is a negative regulatory element that is required for the silencing of unrearranged Igk alleles and thus is involved in establishing or maintaining allelic exclusion. LAD

Immunity 24, 405–415 (2006)

Research notes written by Christine Borowski, Douglas C. Braaten and Laurie A. Dempsey.