
On the cover: Eukaryotic cells rely on aerobic mitochondrial metabolism to generate ATP. Here, Cárdenas et al. (pp. 270–283) demonstrate that constitutive low-level Ca2+ release through endoplasmic reticulum InsP3 receptor release channels (yellow flashes), in close proximity to mitochondria, is essential for mitochondria to produce sufficient ATP and to maintain normal cell bioenergetics. The image is modified from the original artwork of Odra Noel, with her permission (http://www.odranoel.eu).
In This Issue
Available online 22 July 2010.
Mapping Glycosylation Disease Back to the Starting Line
PAGE 203Congenital disorders of glycosylation (CDGs) are a rare but incurable class of developmental syndromes caused by defects in N-linked protein glycosylation. Cantagrel et al. now report that the steroid 5α-reductase type 3 (SRD5A3) gene is mutated in a new type of human CDG. They show that SRD5A3 is required for the synthesis of a critical glycolipid that donates polysaccharides to proteins during glycosylation. Thus, this study sheds new light on an early step of protein N-glycosylation conserved from yeast to humans while also pinpointing a genetic cause of CDG.
TRF2 Cops a Topological Feel during Replication
PAGE 230
Telomeres are essential for chromosome stability. TRF2, a human DNA-binding protein involved in telomere end protection, and its associated exonuclease Apollo are required for telomere integrity during S phase. Ye et al. now report that TRF2 binds to positively supercoiled DNA during replication and functions in conjunction with Apollo to modulate the amount of topoisomerase 2 needed to release the positive superhelical stress created by fork progression. These findings link telomere end protection with replication via sensing of DNA topology.
Circumventing RA Resistance in Neuroblastoma
PAGE 218
Retinoic acid (RA) induces differentiation of neuroblastoma cells, but its clinical benefit is variable. Hölzel et al. identify crosstalk between the tumor suppressor NF1 and RA-induced differentiation in neuroblastoma. Loss of NF1 activates RAS-MEK signaling, which in turn represses ZNF423, a critical transcriptional coactivator of the RA receptors. Neuroblastomas with low levels of NF1 and/or ZNF423 fail to respond to RA and have an extremely poor outcome. Inhibition of MEK signaling downstream of NF1 restores responsiveness to RA, suggesting a therapeutic strategy to overcome RA resistance in NF1-deficient neuroblastomas.
Dmc Runs Cold to Hot in Crossovers
PAGE 243
Meiotic crossovers are important for proper homolog segregation and are initiated by DNA double-strand breaks (DSBs). Despite the concentration of DSBs in hotspots, crossovers are distributed relatively uniformly along chromosomes. Hyppa and Smith report that in fission yeast this incongruence is due in large part to the use of the sister chromatid, rather than the homolog, for DSB repair at hotspots. Conversely, the homolog is used in regions with few DSBs, so called cold regions. DSB repair in cold regions requires the meiosis-specific strand-transfer protein Dmc1 that is dispensable at hotspots. Partner choice for repair thereby leads to distributed crossover events.
ER Estate Lawyer
PAGE 256
The endoplasmic reticulum (ER) is a gateway for folding and maturation of virtually all secreted and membrane proteins of the cell. ER cannot be generated de novo and must be inherited by daughter cells. Now Babour et al. find that the functional quality of inherited ER is assured during each round of cell division through an ER surveillance mechanism. Cells lacking this mechanism can only sustain a few further rounds of cell division, indicating a critical need for cells to inherit a functionally sound ER.
Calcium Supplement Gives an Energy Boost
PAGE 270
Most eukaryotic cells rely on mitochondrial oxidative phosphorylation as their major source of ATP. Here, Cárdenas et al. demonstrate that constitutive Ca2+ release from the ER to mitochondria mediated by the InsP3R channel has an essential role in maintaining normal levels of oxidative phosphorylation. In its absence, cellular ATP levels fall, inducing AMP kinase-dependent autophagy as a survival mechanism. Constitutive mitochondrial uptake of InsP3R-released Ca2+ is required to maintain sufficient mitochondrial NADH production to support respiration.
Pathogen Effectors Surf into Host Cells on PI3P
PAGE 284
Pathogens of plants and animals produce effector proteins that enter the cytoplasm of host cells to suppress host defenses and enable disease. Now Kale et al. show that effectors of plant pathogens bind cell surface phosphatidylinositol-3-phosphate (PI3P) in order to enter host cells via lipid microdomain-mediated endocytosis. Surprisingly, PI3P was also found on human cells where it could mediate effector entry, suggesting that human and animal pathogens might exploit the same effector entry mechanism. PI3P inhibitors blocked entry into plant and human cells, suggesting new therapeutic strategies against eukaryotic pathogens.
Boning Up on Glucose Homeostasis
PAGE 296 and PAGE 309
Osteocalcin is an osteoblast-derived hormone that promotes insulin secretion and regulates fat deposition. Whether insulin in turn affects osteocalcin activity has been unclear. Now two studies by Fulzele et al. and Ferron et al. demonstrate that insulin signaling in osteoblasts is necessary for whole-body glucose homeostasis and bone resorption via regulation of osteocalcin activity. The authors propose the existence of a bone-pancreas endocrine loop through which insulin signaling in the osteoblast integrates bone remodeling and energy metabolism.
Sirtuin Regulates APP Cleavage
PAGE 320
A hallmark of Alzheimer’s disease (AD) is the accumulation of plaques containing Aβ peptides. The production of Aβ peptides is avoided by cleavage of APP by the α- and γ-secretases. Here Donmez et al. show that production of Aβ peptides in a mouse model of AD is reduced by overexpressing the NAD-dependent deacetylase SIRT1 in brain and is increased by removing SIRT1. SIRT1 activates the gene encoding the α-secretase, ADAM10. These findings indicate that SIRT1 activation may be a viable strategy to combat AD.
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