Necroptosis-like neuronal cell death caused by cellular cholesterol accumulation [Neurobiology]

October 18th, 2016 by Funakoshi, T., Aki, T., Tajiri, M., Unuma, K., Uemura, K.

Aberrant cellular accumulation of cholesterol is associated with neuronal lysosomal storage disorders such as Niemann-Pick disease Type C (NPC). We have shown previously that l-norephedrine (l-Nor), a sympathomimetic amine, induces necrotic cell death associated with massive cytoplasmic vacuolation in SH-SY5Y human neuroblastoma cells. To reveal the molecular mechanism underling necrotic neuronal cell death caused by l-Nor, we examined alterations in the gene expression profile of cells during l-Nor exposure. DNA microarray analysis revealed that the gene levels for cholesterol transport (LDL receptor and NPC2) as well as cholesterol biosynthesis (mevalonate pathway enzymes) are increased after exposure to 3 mM l-Nor for ~6 hours. Concomitant with this observation, the master transcriptional regulator of cholesterol homeostasis, SREBP-2, is activated by l-Nor. The increase in cholesterol uptake as well as biosynthesis is not accompanied by an increase in cholesterol in the plasma membrane, but rather by aberrant accumulation in cytoplasmic compartments. We also found that cell death by l-Nor can be suppressed by nec-1s, an inhibitor of a regulated form of necrosis, necroptosis. Abrogation of SREBP-2 activation by the small molecule inhibitor betulin or by overexpression of dominant negative SREBP-2 efficiently reduces cell death by l-Nor. The mobilization of cellular cholesterol in the presence cyclodextrin (CD) also suppresses cell death. These results were also observed in primary culture of striatum neurons. Taken together, our results indicate that the excessive uptake as well as synthesis of cholesterol should underlie neuronal cell death by l-Nor exposure, and suggest a possible link between lysosomal cholesterol storage disorders and the regulated form of necrosis in neuronal cells.

Proteomics: Fishing for zinc

October 18th, 2016 by Grant Miura

Nature Chemical Biology 12, 889 (2016). doi:10.1038/nchembio.2220

Author: Grant Miura

Protein dynamics: Conformational footprints

October 18th, 2016 by Buyong Ma

Nature Chemical Biology 12, 890 (2016). doi:10.1038/nchembio.2212

Authors: Buyong Ma & Ruth Nussinov

The mechanisms by which proteins evolve new functions can be slow and mysterious. Comprehensive structural analysis of enzyme variants reveal how gradual enrichments of pre-existing populations with the right productive dynamics for new functions can accomplish this aim.

Insulin signaling: At a snail’s pace

October 18th, 2016 by Stéphane Larochelle

Nature Chemical Biology 12, 889 (2016). doi:10.1038/nchembio.2221

Author: Stéphane Larochelle

Long non-coding RNAs: Pulsating RNA motifs

October 18th, 2016 by Terry L. Sheppard

Nature Chemical Biology 12, 889 (2016). doi:10.1038/nchembio.2223

Author: Terry L. Sheppard

Antibiotics: New recipe for targeting resistance

October 18th, 2016 by Balázs Papp

Nature Chemical Biology 12, 891 (2016). doi:10.1038/nchembio.2215

Authors: Balázs Papp & Viktória Lázár

The rapid spread of antibiotic-resistant bacteria demands novel treatment approaches that delay or even reverse the evolution of resistance. A new screening strategy identifies two compounds that select against a common tetracycline-resistance gene in Escherichia coli.

Enzyme mechanisms: Sugary shears

October 18th, 2016 by Ethan D Goddard-Borger

Nature Chemical Biology 12, 892 (2016). doi:10.1038/nchembio.2216

Author: Ethan D Goddard-Borger

Proteolytic maturation of an important transcriptional regulator is performed by a glycosyltransferase. The reaction involves glycosylation of a glutamate residue and conversion of the γ-glycosyl ester product into an N-acyl pyroglutamate, which undergoes spontaneous hydrolysis to effect peptide backbone fission.

Metabolic engineering: Biosensors get the green light

October 18th, 2016 by Sarah K Hammer

Nature Chemical Biology 12, 894 (2016). doi:10.1038/nchembio.2214

Authors: Sarah K Hammer & José L Avalos

A novel approach recruits the largest prokaryotic family of ligand-induced transcriptional regulators to develop a new class of biosensors in yeast based on transcriptional activation, vastly expanding the repertoire of biosensors that could function in eukaryotic hosts.

Synthetic biology: Cholera detectors

October 18th, 2016 by Caitlin Deane

Nature Chemical Biology 12, 889 (2016). doi:10.1038/nchembio.2222

Author: Caitlin Deane

Structural basis of nonribosomal peptide macrocyclization in fungi

October 17th, 2016 by Jinru Zhang

Nature Chemical Biology 12, 1001 (2016). doi:10.1038/nchembio.2202

Authors: Jinru Zhang, Nicholas Liu, Ralph A Cacho, Zhou Gong, Zhu Liu, Wenming Qin, Chun Tang, Yi Tang & Jiahai Zhou

Nonribosomal peptide synthetases (NRPSs) in fungi biosynthesize important pharmaceutical compounds, including penicillin, cyclosporine and echinocandin. To understand the fungal strategy of forging the macrocyclic peptide linkage, we determined the crystal structures of the terminal condensation-like (CT) domain and the holo thiolation (T)-CT complex of Penicillium aethiopicum TqaA. The first, to our knowledge, structural depiction of the terminal module in a fungal NRPS provides a molecular blueprint for generating new macrocyclic peptide natural products.