SUMMARY In Saccharomyces cerevisiae, chemical or genetic inhibition of proteasome activity induces new proteasome synthesis promoted by the transcription factor RPN4. This ensures that proteasome activity is matched to demand. This transcriptional feedback loop is conserved in mammals, but its molecular basis is not understood. Here we report that Nuclear factor erythroid derived 2-related factor 1 (Nrf1), a transcription factor of the cap ‘n’ collar basic leucine zipper family, but not the related Nrf2, is necessary for induced proteasome gene transcription in mouse embryonic fibroblasts (MEFs). Promoter-reporter assays revealed the importance of antioxidant response elements in Nrf1-mediated upregulation of proteasome subunit genes. Nrf1-/- MEFs were impaired in the recovery of proteasome activity after transient treatment with the covalent proteasome inhibitor YU101 and knockdown of Nrf1 in human cancer cells enhanced cell killing by YU101. Taken together, our results suggest that Nrf1-mediated proteasome homeostasis could be an attractive target for therapeutic intervention in cancer.

We compile spectroscopic abundance data from 84 literature sources for 50 elements across 3058 stars in the solar neighborhood, within 150 pc of the Sun, to produce the Hypatia Catalog. We evaluate the variability of the spread in abundance measurements reported for the same star by different surveys. We also explore the likely association of the star within the Galactic disk, the corresponding observation and abundance determination methods for all catalogs in Hypatia, the influence of specific catalogs on the overall abundance trends, and the effect of normalizing all abundances to the same solar scale. The resulting large number of stellar abundance determinations in the Hypatia Catalog are analyzed only for thin-disk stars with observations that are consistent between literature sources. As a result of our large dataset, we find that the stars in the solar neighborhood may be reveal an asymmetric abundance distribution, such that a [Fe/H]-rich group near to the mid-plane is deficient in Mg, Si, S, Ca, Sc II, Cr II, and Ni as compared to stars further from the plane. The Hypatia Catalog has a wide number of applications, including exoplanet hosts, thick and thin disk stars, or stars with different kinematic properties.

Ubiquitylated proteins are degraded by the 26 S protease, an enzyme complex that contains 30 or more unique subunits. One of these proteins, subunit 5a (S5a), has been shown to bind ubiquitin-lysozyme conjugates and free polyubiquitin chains. Using deletional analysis, we have identified in the carboxyl-terminal half of human S5a, two independent polyubiquitin binding sites whose sequences are highly conserved among higher eukaryotic S5a homologs. The sites are approximately 30-amino acids long and are separated by 50 intervening residues. When expressed as small fragments or when present in full-length S5a molecules, the sites differ at least 10-fold in their apparent affinity for polyubiquitin chains. Each binding site contains 5 hydrophobic residues that form an alternating pattern of large and small side chains, e.g. Leu-Ala-Leu-Ala-Leu, and this pattern is essential for binding ubiquitin chains. Based on the importance of the alternating hydrophobic residues in the binding sites and previous studies showing that a hydrophobic patch on the surface of ubiquitin is essential for proteolytic targeting, we propose a model for molecular recognition of polyubiquitin chains by S5a.Ubiquitin is a small, highly conserved eukaryotic protein that can be covalently attached to a variety of cellular proteins including itself (1). Ubiquitylation requires an activating enzyme E1, Ub 1 carrier proteins E2s, and substrate recognition components called E3s (2, 3). Post-translational modification of proteins by ubiquitin may serve several functions. Addition of monomers of ubiquitin to histones or insect actin appears to affect the higher order structure of chromatin or flight muscle, respectively (4, 5). More recently, ubiquitylation has been implicated in endocytosis of the Ste2p yeast mating type receptor (6), and ubiquitin has been proposed to serve a novel nonproteolytic role in the regulated activation of I␤␣ kinase (7). However, the best characterized function of ubiquitin is to promote the degradation of proteins to which it is attached especially when substrates are bound to a polyubiquitin chain rather than individual ubiquitin moieties (8). Polyubiquitin chains are formed by isopeptide linkages involving the C-terminal glycine (Gly 76 ) of one ubiquitin and a lysine ⑀ amino group on another. A ␤-galactosidase fusion protein covalently attached to a polyubiquitin chain consisting of 8 -12 ubiquitins linked by Gly 76 -Lys 48 isopeptide bonds is degraded approximately 10 times more rapidly than the monoubiquitylated substrate (8).The 26 S protease, which was discovered by its ability to degrade ubiquitin-lysozyme conjugates (9), is now known to be formed from two particles, the 19 S regulatory complex (10 -13) and the 20 S proteasome (14, 15). The regulatory complex confers substrate recognition and energy dependence upon the 26 S enzyme, and the proteasome provides proteolytic activities. Although the 26 S protease has been shown to degrade native unmodified ornithine decarboxylase (16), this enzyme of polyamine metab...

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