Cell Reports

Journal: Cell Reports

Abbreviation

Cell Rep

Publisher

Cell Press

ISSN

2666-3864
2211-1247

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Publications1 - 10 of 104

Synthesis of Isomeric Phosphoubiquitin Chains Reveals that Phosphorylation Controls Deubiquitinase Activity and Specificity
Huguenin-Dezot, Nicolas; De Cesare, Virginia; Peltier, Julien; et al. (2016)
Cell Reports
Ubiquitin is post-translationally modified by phosphorylation at several sites, but the consequences of these modifications are largely unknown. Here, we synthesize multi-milligram quantities of ubiquitin phosphorylated at serine 20, serine 57, and serine 65 via genetic code expansion. We use these phosphoubiquitins for the enzymatic assembly of 20 isomeric phosphoubiquitin dimers, with different sites of isopeptide linkage and/or phosphorylation. We discover that phosphorylation of serine 20 on ubiquitin converts UBE3C from a dual-specificity E3 ligase into a ligase that primarily synthesizes K48 chains. We profile the activity of 31 deubiquitinases on the isomeric phosphoubiquitin dimers in 837 reactions, and we discover that phosphorylation at distinct sites in ubiquitin can activate or repress cleavage of a particular linkage by deubiquitinases and that phosphorylation at a single site in ubiquitin can control the specificity of deubiquitinases for distinct ubiquitin linkages.
MZT Proteins Form Multi-Faceted Structural Modules in the γ-Tubulin Ring Complex
Wieczorek, Michal; Huang, Tzu-Lun; Urnavicius, Linas; et al. (2020)
Cell Reports
Microtubule organization depends on the g-tubulin ring complex (g-TuRC), a 2.3-MDa nucleation factor comprising an asymmetric assembly of g-tubulin and GCP2-GCP6. However, it is currently unclear how the g-TuRC-associated microproteins MZT1 and MZT2 contribute to the structure and regulation of the holocomplex. Here, we report cryo-EM structures of MZT1 and MZT2 in the context of the native human g-TuRC. MZT1 forms two subcomplexes with the N-terminal a-helical domains of GCP3 or GCP6 (GCP-NHDs) within the g-TuRC ‘‘lumenal bridge.’’ We determine the X-ray structure of recombinant MZT1/GCP6-NHD and find it is similar to that within the native g-TuRC. We identify two additional MZT/GCP-NHD-like subcomplexes, one of which is located on the outer face of the g-TuRC and comprises MZT2 and GCP2-NHD in complex with a centrosomin motif 1 (CM1)-containing peptide. Our data reveal how MZT1 and MZT2 establish multi-faceted, structurally mimetic ‘‘modules’’ that can expand structural and regulatory interfaces in the g-TuRC.
FoxM1 coordinates cell division, protein synthesis, and mitochondrial activity in a subset of β cells during acute metabolic stress
Kobiita, Ahmad; Silva, Pamuditha N.; Schmid, Marc W.; et al. (2023)
Cell Reports
Pancreatic β cells display functional and transcriptional heterogeneity in health and disease. The sequence of events leading to β cell heterogeneity during metabolic stress is poorly understood. Here, we characterize β cell responses to early metabolic stress in vivo by employing RNA sequencing (RNA-seq), assay for transposase-accessible chromatin with sequencing (ATAC-seq), single-cell RNA-seq (scRNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq), and real-time imaging to decipher temporal events of chromatin remodeling and gene expression regulating the unfolded protein response (UPR), protein synthesis, mitochondrial function, and cell-cycle progression. We demonstrate that a subpopulation of β cells with active UPR, decreased protein synthesis, and insulin secretary capacities is more susceptible to proliferation after insulin depletion. Alleviation of endoplasmic reticulum (ER) stress precedes the progression of the cell cycle and mitosis and ensures appropriate insulin synthesis. Furthermore, metabolic stress rapidly activates key transcription factors including FoxM1, which impacts on proliferative and quiescent β cells by regulating protein synthesis, ER stress, and mitochondrial activity via direct repression of mitochondrial-encoded genes.
Prospective and retrospective representations of saccadic movements in primate prefrontal cortex
Calangiu, Ioana; Kollmorgen, Sepp; Reppas, John; et al. (2025)
Cell Reports
The dorso-lateral prefrontal cortex (dlPFC) contributes to flexible, goal-directed behaviors. However, a coherent picture of dlPFC function is lacking, as its activity is often studied only in relation to a few events within a fully learned behavioral task. Here we obtain a comprehensive description of dlPFC activity across different task epochs, saccade types, tasks, and learning stages. We consistently observe the strongest modulation of neural activity in relation to a retrospective representation of the most recent saccade. Prospective, planning-like activity is limited to task-related, delayed saccades directly eligible for a reward. The link between prospective and retrospective representations is highly structured, potentially reflecting a hard-wired feature of saccade responses. Only prospective representations are modulated by the recent behavioral history, but neither representation is modulated by day-to-day behavioral improvements. The dlPFC thus combines tightly linked flexible and rigid representations with a dominant contribution from retrospective signals maintaining the memory of past actions.
Thyroid hormones are required for thermogenesis of beige adipocytes induced by Zfp423 inactivation
Roth, Lisa; Hoffmann, Anne; Hagemann, Tobias; et al. (2024)
Cell Reports
The significance of thyroid hormones (THs) in beige adipocyte thermogenesis remains incompletely understood. We previously reported that THs directly regulate the expression of zinc-finger protein 423 (ZFP423), an anti-thermogenic factor, in adipose tissue. This study investigates the interaction between THs and adrenergic signaling in regulating thermogenic capacity and activation of beige adipocytes formed in response to Zfp423 deletion. We demonstrate that THs are indispensable for uncoupling protein 1 (UCP1)-dependent thermogenesis, leading to increased energy expenditure in mice with adipocyte-specific Zfp423 knockout. Targeted activation of the thyroid receptor isoform TRβ, which plays a central role in the inguinal depot, is sufficient to enhance energy expenditure in hypothyroid Zfp423iAKO mice. Mechanistically, THs and ZFP423 pathways cooperate to regulate early B cell factor 2 (EBF2)-mediated activation of the Ucp1 gene. RNA sequencing (RNA-seq) analysis of human adipose tissue samples supports the relevance of this regulatory network for human adipose tissue plasticity.
Genomic determinants of protein abundance variation in colorectal cancer cells
Roumeliotis, Theodoros I.; Williams, Steven P.; Gonçalves, Emanuel; et al. (2017)
Cell Reports
Assessing the impact of genomic alterations on protein networks is fundamental in identifying the mechanisms that shape cancer heterogeneity. We have used isobaric labeling to characterize the proteomic landscapes of 50 colorectal cancer cell lines and to decipher the functional consequences of somatic genomic variants. The robust quantification of over 9,000 proteins and 11,000 phosphopeptides on average enabled the de novo construction of a functional protein correlation network, which ultimately exposed the collateral effects of mutations on protein complexes. CRISPR-cas9 deletion of key chromatin modifiers confirmed that the consequences of genomic alterations can propagate through protein interactions in a transcript-independent manner. Lastly, we leveraged the quantified proteome to perform unsupervised classification of the cell lines and to build predictive models of drug response in colorectal cancer. Overall, we provide a deep integrative view of the functional network and the molecular structure underlying the heterogeneity of colorectal cancer cells.
Identification of the Trichome Patterning Core Network Using Data from Weak ttg1 Alleles to Constrain the Model Space
Balkunde, Rachappa; Deneer, Anna; Bechtel, Hanna; et al. (2020)
Cell Reports
The regular distribution of trichomes on leaves in Arabidopsis is a well-understood model system for two-dimensional pattern formation. It involves more than 10 genes and is governed by two patterning principles, the activator-inhibitor (AI) and the activator-depletion (AD) mechanisms, though their relative contributions are unknown. The complexity of gene interactions, protein interactions, and intra- and intercellular mobility of proteins makes it very challenging to understand which aspects are relevant for pattern formation. In this study, we use global mathematical methods combined with a constraining of data to identify the structure of the underlying network. To constrain the model, we perform a genetic, cell biological, and biochemical study of weak ttg1 alleles. We find that the core of trichome patterning is a combination of AI and AD mechanisms differentiating between two pathways activating the long-range inhibitor CPC and the short-range inhibitor TRY.
Lesions to the mediodorsal thalamus, but not orbitofrontal cortex, enhance volatility beliefs linked to paranoia
Suthaharan, Praveen; Thompson, Summer L.; Rossi-Goldthorpe, Rosa A.; et al. (2024)
Cell Reports
Beliefs—attitudes toward some state of the environment—guide action selection and should be robust to variability but sensitive to meaningful change. Beliefs about volatility (expectation of change) are associated with paranoia in humans, but the brain regions responsible for volatility beliefs remain unknown. The orbitofrontal cortex (OFC) is central to adaptive behavior, whereas the magnocellular mediodorsal thalamus (MDmc) is essential for arbitrating between perceptions and action policies. We assessed belief updating in a three-choice probabilistic reversal learning task following excitotoxic lesions of the MDmc (n = 3) or OFC (n = 3) and compared performance with that of unoperated monkeys (n = 14). Computational analyses indicated a double dissociation: MDmc, but not OFC, lesions were associated with erratic switching behavior and heightened volatility belief (as in paranoia in humans), whereas OFC, but not MDmc, lesions were associated with increased lose-stay behavior and reward learning rates. Given the consilience across species and models, these results have implications for understanding paranoia.
Glucose stress causes mRNA retention in nuclear Nab2 condensates
Heinrich, Stephanie; Hondele, Maria; Marchand, Désirée; et al. (2024)
Cell Reports
Nuclear mRNA export via nuclear pore complexes is an essential step in eukaryotic gene expression. Although factors involved in mRNA transport have been characterized, a comprehensive mechanistic understanding of this process and its regulation is lacking. Here, we use single-RNA imaging in yeast to show that cells use mRNA retention to control mRNA export during stress. We demonstrate that, upon glucose withdrawal, the essential RNA-binding factor Nab2 forms RNA-dependent condensate-like structures in the nucleus. This co-incides with a reduced abundance of the DEAD-box ATPase Dbp5 at the nuclear pore. Depleting Dbp5, and consequently blocking mRNA export, is necessary and sufficient to trigger Nab2 condensation. The state of Nab2 condensation influences the extent of nuclear mRNA accumulation and can be recapitulated in vitro, where Nab2 forms RNA-dependent liquid droplets. We hypothesize that cells use condensation to regulate mRNA export and control gene expression during stress.
A PKD-MFF signaling axis couples mitochondrial fission to mitotic progression
Pangou, Evanthia; Bielska, Olga; Guerber, Lucile; et al. (2021)
Cell Reports
Mitochondria are highly dynamic organelles subjected to fission and fusion events. During mitosis, mitochondrial fission ensures equal distribution of mitochondria to daughter cells. If and how this process can actively drive mitotic progression remains largely unknown. Here, we discover a pathway linking mitochondrial fission to mitotic progression in mammalian cells. The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells. Phosphorylation of MFF is crucial for chromosome segregation and promotes cell survival by inhibiting adaptation of the mitotic checkpoint. Thus, PKD/MFF-dependent mitochondrial fission is critical for the maintenance of genome integrity during cell division.

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