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Efficiency of interspecies prion transmission decreases as the primary structures of the infectious proteins diverge. Yet, a single prion protein can misfold into multiple infectious conformations, and such differences in “strain conformation” also alter infection specificity. Here, we explored the relationship between prion strains and species barriers by creating distinct synthetic prion forms of...
Reversible, covalent modification with small ubiquitin-related modifier proteins (SUMOs) is known to mediate nuclear import/export and activity of transcription factors. Here, the SUMO pathway is shown to operate at the plasma membrane to control ion channel function. SUMO-conjugating enzyme is seen to be resident in plasma membrane, to assemble with K2P1, and to modify K2P1 lysine 274. K2P1 had not...
Cells communicate with other cells via (trans) interaction between membrane-linked ephrins and Eph receptors. In this issue of Cell, Pfaff and colleagues (Marquardt et al., 2005) demonstrate that coexpressed ephrin-As and Ephs do not interact in cis but rather segregate into separate membrane domains, from which they signal opposing effects during motor axon guidance.
Spongiform encephalopathies are believed to be transmitted by self-perpetuating conformational conversion of the prion protein. It was shown recently that fundamental aspects of mammalian prion propagation can be reproduced in vitro in a seeded fibrillization of the recombinant prion protein variant Y145Stop (PrP23–144). Here we demonstrate that PrP23–144 amyloids from different species adopt distinct...
Optically gated ion channels were expressed in circumscribed groups of neurons in the Drosophila CNS so that broad illumination of flies evoked action potentials only in genetically designated target cells. Flies harboring the “phototriggers” in different sets of neurons responded to laser light with behaviors specific to the sites of phototrigger expression. Photostimulation of neurons in the giant...
Mutually exclusive expression within the var gene family of the malaria parasite Plasmodium falciparum is important for parasite survival and virulence. In this issue of Cell, Duraisingh et al. and Freitas-Junior et al. provide evidence for the role of Sir2-dependent alterations in chromatin structure and changes in subnuclear chromatin localization in regulating var gene expression (Duraisingh et...
Electrical stimulation of neurons in the central nervous system of awake, behaving animals offers the ultimate test to determine whether the activation of specific neurons is sufficient to elicit perception, motor activity, or other behaviors. In this issue of Cell, Lima and Miesenböck (Lima and Miesenböck, 2005) dump the stimulating electrode in favor of a new remote control system to excite specific...
Effects of the cytokine TGF-β can be dampened by E3 ubiquitin ligases that target specific Smads, the TGF-β signal transducers, for proteolytic destruction. Two papers in this issue of Cell highlight the importance of this mechanism in regulating the in vivo effects of TGF-β. The first paper identifies and characterizes a novel Smad4 ubiquitin ligase, and the second paper redefines the role of a previously...
Aging of a eukaryotic organism is affected by its nutrition state and by its ability to prevent or repair oxidative damage. Consequently, signal transduction systems that control metabolism and oxidative stress responses influence life span. When nutrients are abundant, the insulin/IGF signaling (IIS) pathway promotes growth and energy storage but shortens life span. The transcription factor Foxo,...
The malaria parasite Plasmodium falciparum undergoes antigenic variation to evade host immune responses through switching expression of variant surface proteins encoded by the var gene family. We demonstrate that both a subtelomeric transgene and var genes are subject to reversible gene silencing. Var gene silencing involves the SIR complex as gene disruption of PfSIR2 results in activation of this...
Hair graying is an obvious sign of human aging, yet little was known about its causes. Two recent papers provide compelling evidence that hair graying is due to incomplete melanocyte stem cell maintenance and identify Pax3 and Mitf as key molecules that help regulate the balance between melanocyte stem cell maintenance and differentiation.
TGF-β signaling is essential for development and proliferative homeostasis. During embryogenesis, maternal determinants act in concert with TGF-β signals to form mesoderm and endoderm. In contrast, ectoderm specification requires the TGF-β response to be attenuated, although the mechanisms by which this is achieved remain unknown. In a functional screen for ectoderm determinants, we have identified...
Factors controlling the onset and progression of extracellular amyloid diseases remain largely unknown. Central to disease etiology is the efficiency of the endoplasmic reticulum (ER) machinery that targets destabilized mutant proteins for degradation and the enhanced tendency of these variants to aggregate if secreted. We demonstrate that mammalian cells secrete numerous transthyretin (TTR) disease-associated...
Bone is constantly resorbed and formed throughout life by coordinated actions of osteoclasts and osteoblasts. Here we show that Smurf1, a HECT domain ubiquitin ligase, has a specific physiological role in suppressing the osteogenic activity of osteoblasts. Smurf1-deficient mice are born normal but exhibit an age-dependent increase of bone mass. The cause of this increase can be traced to enhanced...
Malaria parasites use antigenic variation to avoid immune clearance and increase the duration of infection in the human host. Variation at the surface of P. falciparum-infected erythrocytes is mediated by the differential control of a family of surface antigens encoded by var genes. Switching of var gene expression occurs in situ, mostly from telomere-associated loci, without detectable DNA alterations,...
Contact-dependent signaling between membrane-linked ligands and receptors such as the ephrins and Eph receptor tyrosine kinases controls a wide range of developmental and pathological processes. Paradoxically, many cell types coexpress both ligands and receptors, raising the question of how specific signaling readouts are achieved under these conditions. Here, we studied the signaling activities exerted...
The bacterial toxin pneumolysin is released as a soluble monomer that kills target cells by assembling into large oligomeric rings and forming pores in cholesterol-containing membranes. Using cryo-EM and image processing, we have determined the structures of membrane-surface bound (prepore) and inserted-pore oligomer forms, providing a direct observation of the conformational transition into the pore...
Crystal structures of H. marismortui large ribosomal subunits containing the mutation G2099A (A2058 in E. coli) with erythromycin, azithromycin, clindamycin, virginiamycin S, and telithromycin bound explain why eubacterial ribosomes containing the mutation A2058G are resistant to them. Azithromycin binds almost identically to both G2099A and wild-type subunits, but the erythromycin affinity increases...
Prions are unconventional infectious agents responsible for transmissible spongiform encephalopathy (TSE) diseases. They are thought to be composed exclusively of the protease-resistant prion protein (PrP res ) that replicates in the body by inducing the misfolding of the cellular prion protein (PrP C ). Although compelling evidence supports this hypothesis, generation of infectious...
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