A Functional Dissection of the mRNA and Locally Synthesized Protein Population in Neuronal Dendrites and Axons

2021 ◽  
Vol 55 (1) ◽  
Author(s):  
Julio D. Perez ◽  
Claudia M. Fusco ◽  
Erin M. Schuman
Keyword(s):  
Messenger Rna ◽  
Mrna Translation ◽  
Annual Review ◽  
Publication Date ◽  
Cellular Functions ◽  
Protein Levels ◽  
Neuronal Dendrites ◽  
Subcellular Compartments ◽  
Specialized Organization ◽  
Local Protein

Neurons are characterized by a complex morphology that enables the generation of subcellular compartments with unique biochemical and biophysical properties, such as dendrites, axons, and synapses. To sustain these different compartments and carry a wide array of elaborate operations, neurons express a diverse repertoire of gene products. Extensive regulation at both the messenger RNA (mRNA) and protein levels allows for the differentiation of subcellular compartments as well as numerous forms of plasticity in response to variable stimuli. Among the multiple mechanisms that control cellular functions, mRNA translation is manipulated by neurons to regulate where and when a protein emerges. Interestingly, transcriptomic and translatomic profiles of both dendrites and axons have revealed that the mRNA population only partially predicts the local protein population and that this relation significantly varies between different gene groups. Here, we describe the space that local translation occupies within the large molecular and regulatory complexity of neurons, in contrast to other modes of regulation. We then discuss the specialized organization of mRNAs within different neuronal compartments, as revealed by profiles of the local transcriptome. Finally, we discuss the features and functional implications of both locally correlated—and anticorrelated—mRNA-protein relations both under baseline conditions and during synaptic plasticity. Expected final online publication date for the Annual Review of Genetics, Volume 55 is November 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Receptor-Ribosome Coupling: A Link Between Extrinsic Signals and mRNA Translation in Neuronal Compartments

2022 ◽  
Vol 45 (1) ◽  
Author(s):  
Max Koppers ◽  
Christine E. Holt
Keyword(s):  
Intracellular Signaling ◽  
Messenger Rna ◽  
Molecular Mechanisms ◽  
Synapse Formation ◽  
Cell Communication ◽  
Mrna Translation ◽  
Common Mechanism ◽  
Annual Review ◽  
Publication Date ◽  
Spatiotemporal Resolution

Axons receive extracellular signals that help to guide growth and synapse formation during development and to maintain neuronal function and survival during maturity. These signals relay information via cell surface receptors that can initiate local intracellular signaling at the site of binding, including local messenger RNA (mRNA) translation. Direct coupling of translational machinery to receptors provides an attractive way to activate this local mRNA translation and change the local proteome with high spatiotemporal resolution. Here, we first discuss the increasing evidence that different external stimuli trigger translation of specific subsets of mRNAs in axons via receptors and thus play a prominent role in various processes in both developing and mature neurons. We then discuss the receptor-mediated molecular mechanisms that regulate local mRNA translational with a focus on direct receptor-ribosome coupling. We advance the idea that receptor-ribosome coupling provides several advantages over other translational regulation mechanisms and is a common mechanism in cell communication. Expected final online publication date for the Annual Review of Neuroscience, Volume 45 is July 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PI(4,5)P2 Clustering and Its Impact on Biological Functions

2021 ◽  
Vol 90 (1) ◽  
Author(s):  
Yi Wen ◽  
Volker M. Vogt ◽  
Gerald W. Feigenson
Keyword(s):  
Plasma Membrane ◽  
Cell Biology ◽  
Cellular Proteins ◽  
Annual Review ◽  
Publication Date ◽  
Biological Functions ◽  
Cellular Functions ◽  
Dynamic Distribution ◽  
Multivalent Cation ◽  
Lipid Environment

Located at the inner leaflet of the plasma membrane, phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] comprises only 1–2 mol% of total PM lipids. With its synthesis and turnover both spatially and temporally regulated, PI(4,5)P2 recruits and interacts with hundreds of cellular proteins to support a broad spectrum of cellular functions. Several factors contribute to the versatile and dynamic distribution of PI(4,5)P2 in membranes. Physiological multivalent cations such as Ca2+ and Mg2+ can bridge between PI(4,5)P2 headgroups, forming nanoscopic PI(4,5)P2–cation clusters. The distinct lipid environment surrounding PI(4,5)P2 affects the degree of PI(4,5)P2 clustering. In addition, diverse cellular proteins interacting with PI(4,5)P2 can further regulate PI(4,5)P2 lateral distribution and accessibility. This review summarizes the current understanding of PI(4,5)P2 behavior in both cells and model membranes, with emphasis on both multivalent cation– and protein-induced PI(4,5)P2 clustering. Understanding the nature of spatially separated pools of PI(4,5)P2 is fundamental to cell biology. Expected final online publication date for the Annual Review of Biochemistry, Volume 90 is June 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Single-Cell Epigenomics Reveals Mechanisms of Cancer Progression

2022 ◽  
Vol 6 (1) ◽  
Author(s):  
Lindsay M. LaFave ◽  
Rachel Savage ◽  
Jason D. Buenrostro
Keyword(s):  
Single Cell ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Annual Review ◽  
Publication Date ◽  
Cancer Evolution ◽  
Regulatory State ◽  
Cellular Functions ◽  
Cancer Initiation ◽  
Gene Regulatory

Cancer initiation is driven by the cooperation between genetic and epigenetic aberrations that disrupt gene regulatory programs critical to maintain specialized cellular functions. After initiation, cells acquire additional genetic and epigenetic alterations influenced by tumor-intrinsic and -extrinsic mechanisms, which increase intratumoral heterogeneity, reshape the cell's underlying gene regulatory network, and promote cancer evolution. Furthermore, environmental or therapeutic insults drive the selection of heterogeneous cell states, with implications for cancer initiation, maintenance, and drug resistance. The advancement of single-cell genomics has begun to uncover the full repertoire of chromatin and gene expression states (cell states) that exist within individual tumors. These single-cell analyses suggest that cells diversify in their regulatory states upon transformation by co-opting damage-induced and nonlineage regulatory programs that can lead to epigenomic plasticity. Here, we review these recent studies related to regulatory state changes in cancer progression and highlight the growing single-cell epigenomics toolkit poised to address unresolved questions in the field. Expected final online publication date for the Annual Review of Cancer Biology, Volume 6 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Dendritic LSm1/CBP80-mRNPs mark the early steps of transport commitment and translational control

2009 ◽  
Vol 184 (3) ◽  
pp. 423-435 ◽  
Author(s):  
Alessandra di Penta ◽  
Valentina Mercaldo ◽  
Fulvio Florenzano ◽  
Sebastian Munck ◽  
M. Teresa Ciotti ◽  
...  
Keyword(s):  
Nuclear Localization ◽  
Translational Control ◽  
Messenger Rna ◽  
Translational Regulation ◽  
Mrna Synthesis ◽  
Local Protein Synthesis ◽  
Neuronal Dendrites ◽  
The Central Nervous System ◽  
Local Protein ◽  
Stimulation Of

Messenger RNA (mRNA) transport to neuronal dendrites is crucial for synaptic plasticity, but little is known of assembly or translational regulation of dendritic messenger ribonucleoproteins (mRNPs). Here we characterize a novel mRNP complex that is found in neuronal dendrites throughout the central nervous system and in some axonal processes of the spinal cord. The complex is characterized by the LSm1 protein, which so far has been implicated in mRNA degradation in nonneuronal cells. In brain, it associates with intact mRNAs. Interestingly, the LSm1-mRNPs contain the cap-binding protein CBP80 that associates with (pre)mRNAs in the nucleus, suggesting that the dendritic LSm1 complex has been assembled in the nucleus. In support of this notion, neuronal LSm1 is partially nuclear and inhibition of mRNA synthesis increases its nuclear localization. Importantly, CBP80 is also present in the dendrites and both LSm1 and CBP80 shift significantly into the spines upon stimulation of glutamergic receptors, suggesting that these mRNPs are translationally activated and contribute to the regulated local protein synthesis.

The Bacterial Hsp90 Chaperone: Cellular Functions and Mechanism of Action

2021 ◽  
Vol 75 (1) ◽  
Author(s):  
Sue Wickner ◽  
Thu-Lan Lily Nguyen ◽  
Olivier Genest
Keyword(s):  
Molecular Chaperone ◽  
Conformational Dynamics ◽  
Heat Shock Protein 90 ◽  
Annual Review ◽  
Publication Date ◽  
Cellular Functions ◽  
Hsp90 Chaperone ◽  
Client Proteins ◽  
Protein Remodeling ◽  
Substrate Proteins

Heat shock protein 90 (Hsp90) is a molecular chaperone that folds and remodels proteins, thereby regulating the activity of numerous substrate proteins. Hsp90 is widely conserved across species and is essential in all eukaryotes and in some bacteria under stress conditions. To facilitate protein remodeling, bacterial Hsp90 collaborates with the Hsp70 molecular chaperone and its cochaperones. In contrast, the mechanism of protein remodeling performed by eukaryotic Hsp90 is more complex, involving more than 20 Hsp90 cochaperones in addition to Hsp70 and its cochaperones. In this review, we focus on recent progress toward understanding the basic mechanisms of bacterial Hsp90-mediated protein remodeling and the collaboration between Hsp90 and Hsp70. We describe the universally conserved structure and conformational dynamics of these chaperones and their interactions with one another and with client proteins. The physiological roles of Hsp90 in Escherichia coli and other bacteria are also discussed. We anticipate that the information gained from exploring the mechanism of the bacterial chaperone system will provide a framework for understanding the more complex eukaryotic Hsp90 system. Expected final online publication date for the Annual Review of Microbiology, Volume 75 is October 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Mitochondria and Inflammatory Bowel Diseases: Toward a Stratified Therapeutic Intervention

2021 ◽  
Vol 84 (1) ◽  
Author(s):  
Gwo-tzer Ho ◽  
Arianne L. Theiss
Keyword(s):  
Mitochondrial Dysfunction ◽  
Intestinal Inflammation ◽  
Critical Role ◽  
Annual Review ◽  
Publication Date ◽  
Cellular Functions ◽  
Targeted Interventions ◽  
Bowel Diseases ◽  
Key Factor ◽  
Inflammatory Bowel

Mitochondria serve numerous critical cellular functions, rapidly responding to extracellular stimuli and cellular demands while dynamically communicating with other organelles. Mitochondrial function in the gastrointestinal epithelium plays a critical role in maintaining intestinal health. Emerging studies implicate the involvement of mitochondrial dysfunction in inflammatory bowel disease (IBD). This review presents mitochondrial metabolism, function, and quality control that converge in intestinal epithelial stemness, differentiation programs, barrier integrity, and innate immunity to influence intestinal inflammation. Intestinal and disease characteristics that set the stage for mitochondrial dysfunction being a key factor in IBD, and in turn, pathogenic mitochondrial mechanisms influencing and potentiating the development of IBD, are discussed. These findings establish the basis for potential mitochondrial-targeted interventions for IBD therapy. Expected final online publication date for the Annual Review of Physiology, Volume 84 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Adenosine Deaminases Acting on RNA (ADARs) and Viral Infections

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Christian K. Pfaller ◽  
Cyril X. George ◽  
Charles E. Samuel
Keyword(s):  
Messenger Rna ◽  
Measles Virus ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Annual Review ◽  
Publication Date ◽  
Alternative Promoters ◽  
Hepatitis D ◽  
Alu Elements ◽  
Adenosine Deaminases

C6 deamination of adenosine (A) to inosine (I) in double-stranded RNA (dsRNA) is catalyzed by a family of enzymes known as ADARs (adenosine deaminases acting on RNA) encoded by three genes in mammals. Alternative promoters and splicing produce two ADAR1 proteins, an interferon-inducible cytoplasmic p150 and a constitutively expressed p110 that like ADAR2 is a nuclear enzyme. ADAR3 lacks deaminase activity. A-to-I editing occurs with both viral and cellular RNAs. Deamination activity is dependent on dsRNA substrate structure and regulatory RNA-binding proteins and ranges from highly site selective with hepatitis D RNA and glutamate receptor precursor messenger RNA (pre-mRNA) to hyperediting of measles virus and polyomavirus transcripts and cellular inverted Alu elements. Because I base-pairs as guanosine instead of A, editing can alter mRNA decoding, pre-mRNA splicing, and microRNA silencing. Editing also alters dsRNA structure, thereby suppressing innate immune responses including interferon production and action. Expected final online publication date for the Annual Review of Virology, Volume 8 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Synbiotic-associated improvement in liver function in cirrhotic patients: Relation to changes in circulating cytokine messenger RNA and protein levels

2007 ◽  
Vol 19 (1) ◽  
Author(s):  
Stephen M. Riordan ◽  
Narelle A. Skinner ◽  
Christopher J. Mciver ◽  
Qing Liu ◽  
Stig Bengmark ◽  
...  
Keyword(s):  
Liver Function ◽  
Messenger Rna ◽  
Protein Levels ◽  
Cirrhotic Patients

scholarly journals Interactions of the Streptococcus pneumoniae Toxin-Antitoxin RelBE Proteins with Their Target DNA

2021 ◽  
Vol 9 (4) ◽  
pp. 851
Author(s):  
Inmaculada Moreno-Córdoba ◽  
Wai-Ting Chan ◽  
Concha Nieto ◽  
Manuel Espinosa
Keyword(s):  
Streptococcus Pneumoniae ◽  
Self Regulation ◽  
Mrna Translation ◽  
Dna Supercoiling ◽  
Bacterial Toxin ◽  
Type Ii ◽  
Cellular Functions ◽  
Dna Backbone ◽  
Different Strains ◽  
Palindromic Sequences

Type II bacterial toxin-antitoxin (TA) systems are found in most bacteria, archaea, and mobile genetic elements. TAs are usually found as a bi-cistronic operon composed of an unstable antitoxin and a stable toxin that targets crucial cellular functions like DNA supercoiling, cell-wall synthesis or mRNA translation. The type II RelBE system encoded by the pathogen Streptococcus pneumoniae is highly conserved among different strains and participates in biofilm formation and response to oxidative stress. Here, we have analyzed the participation of the RelB antitoxin and the RelB:RelE protein complex in the self-regulation of the pneumococcal relBE operon. RelB acted as a weak repressor, whereas RelE performed the role of a co-repressor. By DNA footprinting experiments, we show that the proteins bind to a region that encompasses two palindromic sequences that are located around the −10 sequences of the single promoter that directs the synthesis of the relBE mRNA. High-resolution footprinting assays showed the distribution of bases whose deoxyriboses are protected by the bound proteins, demonstrating that RelB and RelB:RelE contacted the DNA backbone on one face of the DNA helix and that these interactions extended beyond the palindromic sequences. Our findings suggest that the binding of the RelBE proteins to its DNA target would lead to direct inhibition of the binding of the host RNA polymerase to the relBE promoter.

scholarly journals PBRM1 Cooperates with YTHDF2 to Control HIF-1α Protein Translation

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1425
Author(s):  
Alena Shmakova ◽  
Mark Frost ◽  
Michael Batie ◽  
Niall S. Kenneth ◽  
Sonia Rocha
Keyword(s):  
Protein Expression ◽  
Cellular Response ◽  
Transcriptional Activity ◽  
Mrna Translation ◽  
Protein Translation ◽  
Signalling Pathways ◽  
Independent Function ◽  
Protein Levels ◽  
Associated Proteins ◽  
Core Components

PBRM1, a component of the chromatin remodeller SWI/SNF, is often deleted or mutated in human cancers, most prominently in renal cancers. Core components of the SWI/SNF complex have been shown to be important for the cellular response to hypoxia. Here, we investigated how PBRM1 controls HIF-1α activity. We found that PBRM1 is required for HIF-1α transcriptional activity and protein levels. Mechanistically, PBRM1 is important for HIF-1α mRNA translation, as absence of PBRM1 results in reduced actively translating HIF-1α mRNA. Interestingly, we found that PBRM1, but not BRG1, interacts with the m6A reader protein YTHDF2. HIF-1α mRNA is m6A-modified, bound by PBRM1 and YTHDF2. PBRM1 is necessary for YTHDF2 binding to HIF-1α mRNA and reduction of YTHDF2 results in reduced HIF-1α protein expression in cells. Our results identify a SWI/SNF-independent function for PBRM1, interacting with HIF-1α mRNA and the epitranscriptome machinery. Furthermore, our results suggest that the epitranscriptome-associated proteins play a role in the control of hypoxia signalling pathways.

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