Background: NR5A nuclear receptors are important pharmaceutical targets with poorly understood ligand regulation. Sequence divergence has potentially altered their ligand response in model organisms.
Results: Sequence divergence has differentially impacted ligand binding and protein dynamics in NR5A orthologs.
Conclusion: Mouse LRH-1 is a phospholipid-responsive receptor, whereas Drosophila NR5A2 is not.
Significance: Mice are viable therapeutic models for LRH-1-dependent diseases.
Background:
Proteolytic degradation of epithelial sodium channels (ENaC) assists in regulating net salt and water balance in lung epithelia.
Results:
H2O2 increases surface expression of α-ENaC, transepithelial Na transport, and alveolar fluid clearance via redox-sensitive Nedd8.
Conclusion:
Redox-sensitive Nedd8 is involved in the ubiquitination of lung ENaC.
Significance:
Understanding ROS-mediated signaling of lung ENaC is crucial for understanding pulmonary physiology and pathology.
The redox proteome consists of reversible and irreversible covalent modifications that link redox metabolism to biologic structure and function. These modifications, especially of Cys, function at the molecular level in protein folding and maturation, catalytic activity, signaling, and macromolecular interactions and at the macroscopic level in control of secretion and cell shape. Interaction of the redox proteome with redox-active chemicals is central to macromolecular structure, regulation, and signaling during the life cycle and has a central role in the tolerance and adaptability to diet and environmental challenges.
Heat shock proteins are up-regulated as a physiological response to stressful stimuli and generally function as molecular chaperones for improperly folded protein substrates. The small heat shock protein HSP27 (or HSPB1) has multiple cytoplasmic roles. HSP27 also can translocate to the nucleus in response to stress, but the functional significance of this nuclear distribution has not been elucidated. We have previously implicated HSP27 as a genetic modifier of spinocerebellar ataxia 17 (SCA17), a neurological disease caused by a polyglutamine expansion in the TATA-binding protein (TBP). Altered expression of HSP27 is also found in cell models of other polyglutamine diseases, including Huntington disease as well as SCA3 and SCA7. Here, we show that Hsp27, unlike Hsp70, is not detected in mutant TBP aggregates in primary cerebellar granule neurons from transgenic SCA17 mice. Although HSP27 overexpression does not reduce the aggregation of cotransfected mutant TBP containing 105 glutamines, it potentiates activated transcription from both TATA-containing and TATA-lacking promoters. Neither HSP40 nor HSP70 elicits the same transcriptional effect. Moreover, HSP27 interacts with the transcription factor SP1, and coexpression of SP1 and nuclear localization signal-tagged HSP27 synergistically activates reporter constructs for the SP1-responsive neurotrophic receptor genes Ngfrp75 and TRKA. Overexpression of nuclear localization signal-tagged HSP27 also rescues mutant TBP-mediated down-regulation of TrkA in a PC12 cell model of SCA17. These results indicate that nuclear HSP27 can modulate SP1-dependent transcriptional activity to promote neuronal protection.
by
Andrew N. Bankston;
Wenqi Li;
Hui Zhang;
Li Ku;
Guanglu Liu;
Filomena Papa;
Lixia Zhao;
James A. Bibb;
Franca Cambi;
Seema K. Tiwari-Woodruff;
Yue Feng
Background: Cyclin-dependent kinase 5 (Cdk5) is crucial for brain development.
Results: In contrast to neurons that utilize p35 as the primary Cdk5 activator, oligodendroglia employ p39-dependent Cdk5 activation to advance differentiation and myelin repair.
Conclusion: p39 is the primary Cdk5 activator in oligodendroglia, essential for oligodendroglia development.
Significance: Our study revealed distinct mechanisms controlling Cdk5 activity in neurons and oligodendroglia.
Huntington disease (HD) is caused by an expansion of the polyglutamine (polyQ) repeat (>37Q) in huntingtin (htt), and age of onset is inversely correlated with the length of the polyQ repeat. Mutant htt with expanded polyQ is ubiquitously expressed in various types of cells, including glia, but causes selective neurodegeneration. Our recent study demonstrated that expression of the N-terminal mutant htt with a large polyQ repeat (160Q) in astrocytes is sufficient to induce neurological symptoms in mice (Bradford, J., Shin, J. Y., Roberts, M., Wang, C. E., Li, X.-J., and Li, S. H. (2009) Proc. Natl. Acad. Sci. U.S.A. 106, 22480–22485). Because glia-neuron interactions are critical for maintaining the normal function and survival of neurons in the brain and because mutant htt is more abundant in neurons than in glial cells, it is important to investigate whether glial htt can still contribute to HD pathology when mutant htt is abundantly expressed in neuronal cells. We generated transgenic mice that express mutant htt with 98Q in astrocytes. Unlike our recently generated htt-160Q transgenic mice, htt-98Q mice do not show obvious neurological phenotypes, suggesting that the length of the polyQ repeat determines the severity of glial dysfunction. However, htt-98Q mice show increased susceptibility to glutamate-induced seizure. Mice expressing mutant htt in astrocytes were mated with N171-82Q mice that express mutant htt primarily in neuronal cells. Double transgenic mice expressing mutant htt in both neuronal and glial cells display more severe neurological symptoms and earlier death than N171-82Q mice. These findings indicate a role of glial mutant htt in exacerbating HD neuropathology and underscore the importance of improving glial function in treating HD.
Background: Cargo proteins recruit Arf-dependent adaptors for packaging.
Results: Cargo presence at the Golgi/endosomes leads to specific adaptor recruitment.
Conclusion: Arf activation is more closely coupled to cargo than previously appreciated, and we interpret the specificity in adaptor recruitment as evidence of the lack of freely diffusible activated Arfs.
Significance: Cargos play a role in the activation of Arfs and recruitment of specific adaptors.
The T-synthase is the key β3-galactosyltransferase essential for biosynthesis of core 1 O-glycans (Galβ1–3GalNAcα1-Ser/Thr) in animal cell glycoproteins. Here we describe the novel ability of an endoplasmic reticulum-localized molecular chaperone termed Cosmc to specifically interact with partly denatured T-synthase in vitro to cause partial restoration of activity. By contrast, a mutated form of Cosmc observed in patients with Tn syndrome has reduced chaperone function. The chaperone activity of Cosmc is specific, does not require ATP in vitro, and is effective toward T-synthase but not another β-galactosyltransferase. Cosmc represents the first ER chaperone identified to be required for folding of a glycosyltransferase.
Background: Regulation of virus entry by host lipids is poorly understood.
Results: Imaging of low pH-mediated fusion between single vesicular stomatitis pseudoviruses and lipid bilayers revealed a striking reliance on anionic lipids.
Conclusion: The dependence of fusion on late endosome-resident anionic lipids suggests a new means for regulating the virus entry sites.
Significance: Reliance on specific lipids for fusion may shed light on future antiviral strategies.
Background: SAMHD1 is an enzyme that maintains low dNTP concentrations in macrophages.
Results: Depletion of SAMHD1 decreases HIV-1 sensitivity to nucleoside reverse transcriptase inhibitors (NRTIs) in macrophages, but does not significantly alter sensitivity in T cells.
Conclusion: SAMHD1 expression levels in macrophages directly impact the efficacy of NRTIs by modulating cellular dNTP concentrations.
Significance: SAMHD1 controls HIV-1 sensitivity to NRTIs.