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In brief: June 2006Centromeres
The CENP-H–I complex is required for the efficient incorporation of newly synthesized CENP-A into centromeres
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The human CENP-A centromeric nucleosome-associated complex
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Two groups report the identification of a multiprotein complex that is associated with histone variant CENP-A-containing centromeric chromatin. This complex, named NAC (nucleosome-associated complex), comprises known and new kinetochore proteins. Foltz et al. show that NAC recruits a second complex, CAD (CENP-A distal), that contains other novel kinetochore proteins. Disruption of NAC caused defective chromosome alignment and segregation, but did not affect checkpoint signalling. Okada et al. provide evidence that NAC components are required for the efficient incorporation of CENP-A into centromeric chromatin. Cell death
Caspase-9 holoenzyme is a specific and optimal procaspase-3 processing machine
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The apoptosome activates caspase-9 by dimerization
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In the intrinsic apoptotic pathway, the apoptosome complex recruits and activates caspase-9, which subsequently activates effector caspases, such as caspase-3, that execute apoptosis. Two papers now address a long-standing debate on how the apoptosome activates caspase-9. Yin et al. showed that a dimeric caspase-9 construct had greater enzymatic activity than the caspase-9 holoenzyme, which indicates that dimerization is important for its activation. Also, the apoptosome enhances the affinity of caspase-9 for procaspase-3. The findings of Pop et al. also favour the dimerization model. They showed that a hybrid-caspase construct that consists of caspase-8 and the recruitment domain of caspase-9 was sufficient to allow caspase-9-based recruitment to the apoptosome. Autophagy
Loss of autophagy in the central nervous system causes neurodegeneration in mice
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Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice
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Autophagy is a protein-degradation process that is induced by starvation and generates nutrients for survival. Both studies now implicate the loss of autophagy in neurodegeneration. Mice that lacked either the Atg7 (autophagy-related-7) or Atg5 genes specifically in neural cells showed neurological defects and an accumulation of cytoplasmic proteins in inclusion bodies. These findings indicate that autophagy is required for the normal turnover of proteins to avoid the accumulation of abnormal proteins that can disrupt neural function. Phagocytosis
Apoptotic cells promote macrophage survival by releasing the anti-apoptotic mediator sphingosine-1-phosphate
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Phagocytosis of apoptotic cells by macrophages is an integral part of maintaining cellular homeostasis. Once they have engulfed apoptotic cells, macrophages are protected from apoptosis. Weigert et al. have attributed this protection to the release of sphingosine-1-phosphate (S1P) by the apoptotic cell. This protection of macrophages by S1P involves the activation of survival signals that depend on phosphatidylinositol 3-kinase (PI3K), extracellular-signal-regulated kinase (ERK) and calcium. Upregulation of the anti-apoptotic proteins B-cell lymphoma 2 (BCL-2) and BCL-XL, as well as inactivation of the pro-apoptotic protein BCL-2-agonistic of cell death (BAD), are also involved in this protective process. Therefore, apoptotic cells have an active role, through the secretion of S1P, in preventing apoptosis of phagocytes, such as macrophages. Regulatory T cells
Toll-like receptor 2 signaling modulates the function of CD4+CD25+ regulatory T cells
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Given that there are numerous regulatory T-cell populations that suppress T-cell responses, how does successful protective immunity occur in the face of such suppression? Foo Liew and colleagues report that, in a similar manner to effector T cells, naturally occurring regulatory T (TReg) cells express Toll-like receptor 2 (TLR2) and undergo marked proliferation in the presence of the TLR2 ligand bacterial lipoprotein (BLP) and CD3-specific antibody. Importantly, BLP-induced TReg-cell proliferation resulted in a transient loss of suppressive activity and forkhead box P3 (FOXP3) expression. In addition, interleukin-2 produced by BLP-activated effector T cells rendered these cells refractory to TReg-cell-mediated suppression. But, 3 days after BLP-mediated activation, the TReg cells regained FOXP3 expression and suppressive activity, as indicated by their ability, following adoptive transfer, to prevent colitis in immunodeficient mice. Antigen-presenting cells
CD1a+ antigen-presenting cells in human dermis respond rapidly to CCR7 ligands
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Populations of antigen-presenting cells (APCs) that are distinct from Langerhans cells have recently been identified in mouse skin. Now, a similar population of APCs has been found in human skin. Angel et al. describe a population of APCs that express intermediate levels of CD1a+ but not the Langerhans-cell marker CD207 and that is located close to the lymphatic vessels in the upper layers of the dermis. They termed these cells CD1a+ dermal APCs. This population could prime naive CD4+ T cells, owing to expression of MHC class II and co-stimulatory molecules. In a similar manner to Langerhans cells, the CD1a+ dermal APCs expressed CC-chemokine receptor 7 (CCR7) and could migrate in response to CCR7 ligands, which are known to mediate the migration of cells from the skin to the draining lymph nodes. Macrophages
Carbohydrate-independent recognition of collagens by the macrophage mannose receptor
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A hallmark of alternatively activated macrophages is expression of the mannose receptor, which belongs to a family of four endocytic receptors with a common domain structure. The mannose receptor has two known, distinct lectin (carbohydrate-binding) activities, which are mediated by its cysteine-rich domain and multiple C-type lectin-like domains (CTLDs). Located between these two domains is the fibronectin type II (FNII) domain, which is conserved among all mannose-receptor-family members and is important for collagen binding. Martinez-Pomares et al. examined whether the mouse mannose receptor could bind collagen, or if the CTLD- and cysteine-rich-domain-mediated lectin activity was favoured. They found that the mannose receptor could indeed recognize and internalize collagen in a carbohydrate-independent manner, and that the FNII domain mediated this function. This paper describes a third distinct ligand-binding site for the mannose receptor and therefore has important implications for the study of this receptor at the molecular level. Tumour Suppressors
The regulation of exosome secretion: a novel function of the p53 protein
p53 is a transcription factor that is activated in response to cellular stress. Yu et al. have used a proteomics approach to identify proteins that are secreted by cells in a p53-dependent manner after DNA damage. p53 activation was found to increase the secretion of a set of proteins that are encoded by genes that are not transcriptional targets of p53. These proteins are secreted through small vesicles called exosomes. Furthermore, exosome production by cells is regulated by activation of the p53 pathway, so this pathway has a newly-discovered function in the communication between cells. Oncogenes
Reversible kinetic analysis of Myc targets in vivo provides novel insights into Myc-mediated tumorigenesis
The transcription factor MYC is frequently deregulated in human cancers. Lawlor et al. used a reversible-switch transgenic model of MYC-mediated Tumour Immunology
IL-23 promotes tumour incidence and growth
Langowski et al. show the first molecular connection between tumour-associated inflammation and the failure of the adaptive immune response to target tumours. They show that expression of the cytokine IL-23 is increased in human tumours, and that this both promotes the inflammatory response and reduces cytotoxic T-cell infiltration. Inhibition of IL-23 increased tumour infiltration by cytotoxic T-cells, and the growth of transplanted tumours was reduced in mice that were depleted of IL-23. So, anti-IL-23 therapy might prove to be an effective treatment for solid tumours. Drug discovery
A small-molecule screen in C. elegans yields a new calcium channel antagonist.
Caenorhabditis elegans can be used to rapidly identify new small-molecule inhibitors and their targets, both of which are powerful tools for biological analysis and drug discovery. In a screen of 14,100 small molecules, 308 compounds induced a range of phenotypes. Nemadipine A, which is similar to a class of anti-hypertension drugs that antagonize a particular type of calcium channel, caused abnormal morphology and egg-laying defects. A suppressor screen identified egl-19, which encodes the correct type of calcium channel, as a nemadipine A target. Nemadipine A was then used to reveal calcium-channel redundancy in the egg-laying circuitry. Epigenetics
Circadian regulator CLOCK is a histone acetyltransferase.
These authors show that CLOCK — a key component of the circadian pacemaker — has intrinsic histone acetyltransferase (HAT) activity. CLOCK proteins in which an acetyl-coenzyme A binding motif (which is similar at the sequence level to other well-characterized HAT proteins) has been mutated have reduced HAT activity. Their overexpression cannot rescue circadian gene rythmicity in cells in which the endogenous Clock gene has been mutated, demonstrating the importance of chromatin remodelling in circadian gene expression. Neurogenetics
The molecular diversity of Dscam is functionally required for neuronal wiring specificity in Drosophila.
Dscam, the gene that encodes the Down syndrome cell-adhesion molecule, can potentially produce up to 38,016 different protein isoforms by alternative splicing. The authors showed that Dscam is essential for proper axonal branching in the fly, that alleles that could produce 22,176 isoforms did not fully rescue the phenotype, and that expression of individual isoforms has distinct partial-rescue phenotypic effects. This implies that much of the potential isoform diversity that is encoded by this gene is necessary for the differentiation of neurons. | |
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-cell tumorigenesis, in combination with oligonucleotide microarrays, to identify MYC-regulated genes that are responsible for maintaining MYC-dependent tumours. In addition to genes involved in cell proliferation and tumour progression, a proportion of the MYC-regulated genes were found to be 