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Proteostasis regulates protein synthesis, folding and degradation programs to ensure that the integrity of the proteome remains intact. A collection of Commentary, Perspective and Review articles in this issue describe new advances in understanding the mechanisms of proteostasis and how chemical biological approaches can be used to restore protein homeostasis. The cover image depicts a conveyor belt containing a mixture of folded and misfolded proteins, which are surveyed by the protein quality control network. Unfolded proteins are directed through the black window, where they undergo ubiquitin modification (shown by the Ub label) and degradation by the proteasome (depicted here by the shredder). Cover art by Erin Dewalt.
New insights into the regulatory mechanisms of protein folding and turnover are informing the development of chemical tools and small molecules to treat proteostasis disorders.
The ubiquitin-proteasome system (UPS) pervades the biology of eukaryotes. Because it depends on the activity of hundreds of different enzymes and protein-protein interactions, the UPS provides many opportunities for selective modulation of the pathway with small molecules. Here we discuss the principles that underlie the development of effective inhibitors or activators of the pathway. We emphasize insights from structural analysis and describe strategies for evaluating the selectivity of compounds.
A new family of radical halogenases has been discovered that regio- and stereoselectively chlorinates the unactivated carbon center of indolemonoterpenoid substrates without the prerequisite for the substrate to be bound to a protein carrier.
Understanding the mechanisms that determine cell fate under endoplasmic reticulum (ER) stress had been hampered by the lack of models to study unfolded protein response (UPR) adaptive phases. The development of an engineered protein to conditionally induce its misfolding allowed the establishment of a resolvable ER stress condition.
A recent study reveals a new cellular pathway that clears the endoplasmic reticulum of misfolded, GPI-anchored proteins at the onset of endoplasmic reticulum (ER) stress. This mechanism, termed rapid ER stress–induced export, represents a nontranscriptional response to mitigate acute ER stress.
Two studies demonstrate that natural killer T-cell adjuvants, covalently attached to either carbohydrate or peptide epitopes, yield effective vaccines.
Nonheme iron halogenases, or enzymes that perform oxidative halogenations, exist in a variety of biosynthetic pathways and modify substrates attached to carrier proteins. Biochemical evidence defines a chlorinase that breaks this rule, acting on soluble substrates.
Arylquin 1 was identified as a Par-4 secretagogue that binds the cytoskeletal intermediate filament protein vimentin and disrupts Par-4–vimentin interactions. The release of Par-4 promotes the apoptosis of cancer cells.
N6-methyladenosine (m6A) is an abundant eukaryotic RNA modification that regulates mRNA stability. Biochemical analysis and crystallographic visualization of m6A-YTHDC1 interactions establish this YTH family member as an m6A reader and explain its RNA consensus sequence selectivity.
A single-molecule study of the dwell times and other features along the full rotation for the human mitochondrial F1-ATPase positions the catalytic events (ATP binding, Pi release and ATP hydrolysis) and reveals differences from the bacterial system.
Structural and biochemical studies of an acetyltransferase demonstrate that conformational changes differ depending on the ligand bound, indicating that binding cooperativity is more complex than expected.
A vaccine combining an allergen-specific CD8+ T-cell epitope with an invariant natural killer T (iNKT) cell agonist stimulates immune responses in an animal model of asthma. Rather than a typical pattern recognition receptor ligand as adjuvant, the iNKT agonist used was a glycolipid.
A semisynthetic carbohydrate-lipid vaccine that combines a known adjuvant that has been used in disease models with a lipid capable of activating iNKT cells protects against Streptococcus pneumoniae infection in mice.
The use of an endoplasmic reticulum–localized HaloTag system results in protein destabilization and activation of a transient unfolding protein response (UPR) without causing cell death, allowing the examination of later stage UPR events.
A global bioinformatic classification of >11,000 biosynthetic gene clusters from >800 bacterial genomes and cross-correlation with metabolomics data from nearly 200 strains sets the stage for targeted natural product discovery.
A small-molecule activator of procaspase 3, 1541, forms chemical fibrils. shRNA screens, caspase proteomics and small-molecule profiling reveal that these fibrils enter cells through endocytosis and promote a distinctive form of cell death.
Protein engineering strategies introduced mutations into the Axl receptor, which bind and trap the Gas6 ligand with high affinity, preventing the activation of downstream signaling pathways.
Proteostasis is a cellular network that ensures proteome integrity. In this focus issue, we present a collection of articles that discuss how recent advances in chemical biology are improving our mechanistic understanding of proteostasis and are guiding the development of chemical tools and small molecules to probe protein homeostasis.