scholarly journals mRNA Post-Transcriptional Regulation by AU-Rich Element-Binding Proteins in Liver Inflammation and Cancer

2020 ◽  
Vol 21 (18) ◽  
pp. 6648
Author(s):  
Dobrochna Dolicka ◽  
Cyril Sobolewski ◽  
Marta Correia de Sousa ◽  
Monika Gjorgjieva ◽  
Michelangelo Foti
Keyword(s):  
Liver Diseases ◽  
Binding Proteins ◽  
Current Knowledge ◽  
Cellular Processes ◽  
Complex Processes ◽  
Cellular Context ◽  
Inflammatory Processes ◽  
The Stability ◽  
And Function ◽  
Post Transcriptional Regulation

AU-rich element-binding proteins (AUBPs) represent important post-transcriptional regulators of gene expression. AUBPs can bind to the AU-rich elements present in the 3’-UTR of more than 8% of all mRNAs and are thereby able to control the stability and/or translation of numerous target mRNAs. The regulation of the stability and the translation of mRNA transcripts by AUBPs are highly complex processes that occur through multiple mechanisms depending on the cell type and the cellular context. While AUBPs have been shown to be involved in inflammatory processes and the development of various cancers, their important role and function in the development of chronic metabolic and inflammatory fatty liver diseases (FLDs), as well as in the progression of these disorders toward cancers such as hepatocellular carcinoma (HCC), has recently started to emerge. Alterations of either the expression or activity of AUBPs are indeed significantly associated with FLDs and HCC, and accumulating evidence indicates that several AUBPs are deeply involved in a significant number of cellular processes governing hepatic metabolic disorders, inflammation, fibrosis, and carcinogenesis. Herein, we discuss our current knowledge of the roles and functions of AUBPs in liver diseases and cancer. The relevance of AUBPs as potential biomarkers for different stages of FLD and HCC, or as therapeutic targets for these diseases, are also highlighted.

scholarly journals The Putative RNA-Binding Protein Nrp1 Promotes the Loading of Kinesin-14/Klp2 to the Mitotic Spindle and Is Sequestered Into Heat-Induced Protein Aggregates in Fission Yeast

2021 ◽  
Author(s):  
Masashi Yukawa ◽  
Mitsuki Ohishi ◽  
Yusuke Yamada ◽  
Takashi Toda
Keyword(s):  
Fission Yeast ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Protein Aggregates ◽  
Associated Proteins ◽  
Spindle Microtubules ◽  
The Stability ◽  
And Function ◽  
Post Transcriptional Regulation

Cells form a bipolar spindle during mitosis to ensure accurate chromosome segregation. Proper spindle architecture is established by a set of kinesin motors and microtubule-associated proteins. In most eukaryotes, kinesin-5 motors are essential for this process, and genetic or chemical inhibition of their activity leads to the emergence of monopolar spindles and cell death. However, these deficiencies can be rescued by simultaneous inactivation of kinesin-14 motors, as they counteract kinesin-5. We conducted detailed genetic analyses in fission yeast to understand the mechanisms driving spindle assembly in the absence of kinesin-5. Here we show that deletion of the nrp1 gene, which encodes a putative RNA-binding protein with unknown function, can rescue temperature sensitivity caused by cut7-22, a fission yeast kinesin-5 mutant. Interestingly, kinesin-14/Klp2 levels on the spindles in the cut7 mutants were significantly reduced by the nrp1 deletion, although the total levels of Klp2 and the stability of spindle microtubules remained unaffected. Moreover, RNA-binding motifs of Nrp1 are essential for its cytoplasmic localization and function. We have also found that a portion of Nrp1 is spatially and functionally sequestered by chaperone-based protein aggregates upon mild heat stress and limits cell division at high temperatures. We propose that Nrp1 might be involved in post-transcriptional regulation through its RNA-binding ability to promote the loading of Klp2 on the spindle microtubules.

scholarly journals Differential Effects of “Resurrecting” Csp Pseudoproteases during Clostridioides difficile Spore Germination

2019 ◽  
Author(s):  
M. Lauren Donnelly ◽  
Emily R. Forster ◽  
Amy E. Rohlfing ◽  
Aimee Shen
Keyword(s):  
Spore Germination ◽  
Protease Activity ◽  
Bacterial Pathogen ◽  
Catalytic Triad ◽  
Spore Form ◽  
Cellular Processes ◽  
Clostridioides Difficile ◽  
Serine Protease Family ◽  
The Stability ◽  
And Function

AbstractClostridioides difficile is a spore-forming bacterial pathogen that is the leading cause of hospital-acquired gastroenteritis. C. difficile infections begin when its spore form germinates in the vertebrate gut upon sensing bile acids. These germinants induce a proteolytic signaling cascade controlled by three members of the subtilisin-like serine protease family, CspA, CspB, and CspC. Notably, even though CspC and CspA are both pseudoproteases, they are nevertheless required to sense germinants and activate the protease, CspB. Thus, CspC and CspA are part of a growing list of pseudoenzymes that play important roles in regulating cellular processes. However, despite their importance, the structural properties of pseudoenzymes that allow them to function as regulators remain poorly understood. Our recently determined crystal structure of CspC revealed that its degenerate site residues align closely with the catalytic triad of CspB, so in this study we tested whether the ancestral protease activity of the CspC and CspA pseudoproteases could be “resurrected.” Restoring the catalytic triad to these pseudoproteases failed to resurrect their protease activity, although the mutations differentially affected the stability and function of these pseudoproteases. Degenerate site mutations destabilized CspC and impaired spore germination without impacting CspA stability or function. Thus, our results surprisingly reveal that the presence of a catalytic triad does not necessarily predict protease activity. Since close homologs of C. difficile CspA occasionally carry an intact catalytic triad, our results imply that bioinformatics predictions of enzyme activity may overlook pseudoenzymes in some cases.

scholarly journals The interplay of the type II TA system with other processes

2019 ◽  
Author(s):  
Wei Wen-ping ◽  
Jia Wan Zhong ◽  
Yang Min
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Environmental Stress ◽  
Regulatory Mechanism ◽  
Phage Infection ◽  
Type Ii ◽  
System Research ◽  
Cellular Processes ◽  
The Stability ◽  
And Function ◽  
Insight Into

The type II toxin antitoxin (TA) system is the most well-studied TA system and is widely distributed in bacteria, especially pathogens such as Mycobacterium tuberculosis. Type II TA system plays an important role in many cellular processes, including maintaining the stability of mobile genetic elements, and bacterial altruistic suicide in response to nutritional starvation, environmental stress and phage infection. Interactions between toxin proteins and antitoxin proteins are critical for the regulation and function of type II TA systems; indeed, the understanding of their function is mainly derived from interaction and regulation of paired TA system proteins. Nonetheless, investigating interaction between unpaired TA system proteins, and the interaction between TA system proteins and other functional proteins, are becoming more common and have provided new insight into the complexity of its regulatory mechanism. In this review, we outlined the cross-interaction between TA system proteins, and the interaction between TA system proteins and other functional proteins, and we are trying to explain novel mechanism of TA system in the regulation of cellular activities. On this basis, we further discussed the knowledge and physiological implications of the relevant aspects of TA system research.

scholarly journals RNA-Binding Proteins as Regulators of Migration, Invasion and Metastasis in Oral Squamous Cell Carcinoma

2020 ◽  
Vol 21 (18) ◽  
pp. 6835
Author(s):  
Jonas Weiße ◽  
Julia Rosemann ◽  
Vanessa Krauspe ◽  
Matthias Kappler ◽  
Alexander W. Eckert ◽  
...  
Keyword(s):  
Gene Expression ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulation Of Gene Expression ◽  
Invasion And Metastasis ◽  
Protein Coding ◽  
Oral Cancers ◽  
Cellular Processes ◽  
Post Transcriptional Regulation

Nearly 7.5% of all human protein-coding genes have been assigned to the class of RNA-binding proteins (RBPs), and over the past decade, RBPs have been increasingly recognized as important regulators of molecular and cellular homeostasis. RBPs regulate the post-transcriptional processing of their target RNAs, i.e., alternative splicing, polyadenylation, stability and turnover, localization, or translation as well as editing and chemical modification, thereby tuning gene expression programs of diverse cellular processes such as cell survival and malignant spread. Importantly, metastases are the major cause of cancer-associated deaths in general, and particularly in oral cancers, which account for 2% of the global cancer mortality. However, the roles and architecture of RBPs and RBP-controlled expression networks during the diverse steps of the metastatic cascade are only incompletely understood. In this review, we will offer a brief overview about RBPs and their general contribution to post-transcriptional regulation of gene expression. Subsequently, we will highlight selected examples of RBPs that have been shown to play a role in oral cancer cell migration, invasion, and metastasis. Last but not least, we will present targeting strategies that have been developed to interfere with the function of some of these RBPs.

scholarly journals Regulatory effects of post-translational modifications on zDHHC S-acyltransferases

2020 ◽  
Vol 295 (43) ◽  
pp. 14640-14652
Author(s):  
Filip Zmuda ◽  
Luke H. Chamberlain
Keyword(s):  
Drug Targets ◽  
Acyl Chain ◽  
Fatty Acyl ◽  
Fatty Acyl Chain ◽  
Physiological Importance ◽  
Cellular Processes ◽  
Cell Growth And Differentiation ◽  
Regulatory Effects ◽  
The Stability ◽  
And Function

The human zDHHC S-acyltransferase family comprises 23 enzymes that mediate the S-acylation of a multitude of cellular proteins, including channels, receptors, transporters, signaling molecules, scaffolds, and chaperones. This reversible post-transitional modification (PTM) involves the attachment of a fatty acyl chain, usually derived from palmitoyl-CoA, to specific cysteine residues on target proteins, which affects their stability, localization, and function. These outcomes are essential to control many processes, including synaptic transmission and plasticity, cell growth and differentiation, and infectivity of viruses and other pathogens. Given the physiological importance of S-acylation, it is unsurprising that perturbations in this process, including mutations in ZDHHC genes, have been linked to different neurological pathologies and cancers, and there is growing interest in zDHHC enzymes as novel drug targets. Although zDHHC enzymes control a diverse array of cellular processes and are associated with major disorders, our understanding of these enzymes is surprisingly incomplete, particularly with regard to the regulatory mechanisms controlling these enzymes. However, there is growing evidence highlighting the role of different PTMs in this process. In this review, we discuss how PTMs, including phosphorylation, S-acylation, and ubiquitination, affect the stability, localization, and function of zDHHC enzymes and speculate on possible effects of PTMs that have emerged from larger screening studies. Developing a better understanding of the regulatory effects of PTMs on zDHHC enzymes will provide new insight into the intracellular dynamics of S-acylation and may also highlight novel approaches to modulate S-acylation for clinical gain.

scholarly journals RNA-Binding Proteins as Important Regulators of Long Non-Coding RNAs in Cancer

2020 ◽  
Vol 21 (8) ◽  
pp. 2969 ◽  
Author(s):  
Katharina Jonas ◽  
George A. Calin ◽  
Martin Pichler
Keyword(s):  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Rna Stability ◽  
Protein Coding ◽  
Cellular Processes ◽  
Open Questions ◽  
Non Coding Rnas ◽  
The Stability ◽  
Mrna Binding

The majority of the genome is transcribed into pieces of non-(protein) coding RNA, among which long non-coding RNAs (lncRNAs) constitute a large group of particularly versatile molecules that govern basic cellular processes including transcription, splicing, RNA stability, and translation. The frequent deregulation of numerous lncRNAs in cancer is known to contribute to virtually all hallmarks of cancer. An important regulatory mechanism of lncRNAs is the post-transcriptional regulation mediated by RNA-binding proteins (RBPs). So far, however, only a small number of known cancer-associated lncRNAs have been found to be regulated by the interaction with RBPs like human antigen R (HuR), ARE/poly(U)-binding/degradation factor 1 (AUF1), insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), and tristetraprolin (TTP). These RBPs regulate, by various means, two aspects in particular, namely the stability and the localization of lncRNAs. Importantly, these RBPs themselves are commonly deregulated in cancer and might thus play a major role in the deregulation of cancer-related lncRNAs. There are, however, still many open questions, for example regarding the context specificity of these regulatory mechanisms that, in part, is based on the synergistic or competitive interaction between different RBPs. There is also a lack of knowledge on how RBPs facilitate the transport of lncRNAs between different cellular compartments.

scholarly journals Interactions between Myc and Mediators of Inflammation in Chronic Liver Diseases

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Ting Liu ◽  
Yu Zhou ◽  
Kwang Suk Ko ◽  
Heping Yang
Keyword(s):  
Inflammatory Mediators ◽  
Liver Diseases ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Chronic Liver ◽  
Chronic Liver Diseases ◽  
Cellular Events ◽  
Mediators Of Inflammation ◽  
Proliferation And Differentiation ◽  
Inflammatory Processes

Most chronic liver diseases (CLDs) are characterized by inflammatory processes with aberrant expressions of various pro- and anti-inflammatory mediators in the liver. These mediators are the driving force of many inflammatory liver disorders, which often result in fibrosis, cirrhosis, and liver tumorigenesis. c-Myc is involved in many cellular events such as cell growth, proliferation, and differentiation. c-Myc upregulates IL-8, IL-10, TNF-α, and TGF-β, while IL-1, IL-2, IL-4, TNF-α, and TGF-βpromote c-Myc expression. Their interactions play a central role in fibrosis, cirrhosis, and liver cancer. Molecular interference of their interactions offers possible therapeutic potential for CLDs. In this review, current knowledge of the molecular interactions between c-Myc and various well known inflammatory mediators is discussed.

Multifunctional YY1 in Liver Diseases

2017 ◽  
Vol 37 (04) ◽  
pp. 363-376 ◽  
Author(s):  
Shuang Yang ◽  
Jian Zhou ◽  
Weiwu Gao ◽  
Xia Yang ◽  
Di Yang ◽  
...  
Keyword(s):  
Liver Diseases ◽  
Drug Targets ◽  
Current Knowledge ◽  
Cell Types ◽  
Bile Acid Metabolism ◽  
Multifunctional Protein ◽  
Yin Yang 1 ◽  
B Virus ◽  
Cellular Context ◽  
Underlying Mechanisms

AbstractThe transcription factor Yin Yang 1 (YY1) is a multifunctional protein that can activate or repress gene expression, depending on the cellular context. While YY1 is ubiquitously expressed and highly conserved between species, its role varies among the diverse cell types and includes proliferation, differentiation, and apoptosis. Upregulated YY1 expression is found in pathogenic conditions, such as human hepatocellular carcinoma and hepatitis B virus infection, and its roles in the molecular pathogenic mechanisms in liver (i.e., fibrosis, carcinogenesis, viral-induced injury) are currently being elucidated. The most recent studies have revealed that YY1 is deeply involved in such dysregulated cellular metabolisms as glycometabolism, lipid metabolism, and bile acid metabolism, which are all involved in various diseases. In this review, we will summarize the current knowledge on YY1 in liver diseases, providing a focused discussion on the characterized and probable underlying mechanisms, as well as a reasoned evaluation of the potential for YY1-mediated pathology as drug targets in liver disease therapies.

scholarly journals Discrete regions of the kinesin-8 Kip3 tail differentially mediate astral microtubule stability and spindle disassembly

2018 ◽  
Vol 29 (15) ◽  
pp. 1866-1877 ◽  
Author(s):  
Sandeep Dave ◽  
Samuel J. Anderson ◽  
Pallavi Sinha Roy ◽  
Emmanuel T. Nsamba ◽  
Angela R. Bunning ◽  
...  
Keyword(s):  
Dynamic Properties ◽  
Microtubule Dynamics ◽  
Motor Domain ◽  
Spindle Positioning ◽  
Cellular Processes ◽  
Microtubule Stability ◽  
Astral Microtubule ◽  
Cellular Context ◽  
Spindle Disassembly ◽  
The Stability

To function in diverse cellular processes, the dynamic properties of microtubules must be tightly regulated. Cellular microtubules are influenced by a multitude of regulatory proteins, but how their activities are spatiotemporally coordinated within the cell, or on specific microtubules, remains mostly obscure. The conserved kinesin-8 motor proteins are important microtubule regulators, and family members from diverse species combine directed motility with the ability to modify microtubule dynamics. Yet how kinesin-8 activities are appropriately deployed in the cellular context is largely unknown. Here we reveal the importance of the nonmotor tail in differentially controlling the physiological functions of the budding yeast kinesin-8, Kip3. We demonstrate that the tailless Kip3 motor domain adequately governs microtubule dynamics at the bud tip to allow spindle positioning in early mitosis. Notably, discrete regions of the tail mediate specific functions of Kip3 on astral and spindle microtubules. The region proximal to the motor domain operates to spatially regulate astral microtubule stability, while the distal tail serves a previously unrecognized role to control the timing of mitotic spindle disassembly. These findings provide insights into how nonmotor tail domains differentially control kinesin functions in cells and the mechanisms that spatiotemporally control the stability of cellular microtubules.

scholarly journals Differential effects of ‘resurrecting' Csp pseudoproteases during Clostridioides difficile spore germination

2020 ◽  
Vol 477 (8) ◽  
pp. 1459-1478
Author(s):  
M. Lauren Donnelly ◽  
Emily R. Forster ◽  
Amy E. Rohlfing ◽  
Aimee Shen
Keyword(s):  
Spore Germination ◽  
Protease Activity ◽  
Bacterial Pathogen ◽  
Catalytic Triad ◽  
Spore Form ◽  
Cellular Processes ◽  
Clostridioides Difficile ◽  
Serine Protease Family ◽  
The Stability ◽  
And Function

Clostridioides difficile is a spore-forming bacterial pathogen that is the leading cause of hospital-acquired gastroenteritis. C. difficile infections begin when its spore form germinates in the gut upon sensing bile acids. These germinants induce a proteolytic signaling cascade controlled by three members of the subtilisin-like serine protease family, CspA, CspB, and CspC. Notably, even though CspC and CspA are both pseudoproteases, they are nevertheless required to sense germinants and activate the protease, CspB. Thus, CspC and CspA are part of a growing list of pseudoenzymes that play important roles in regulating cellular processes. However, despite their importance, the structural properties of pseudoenzymes that allow them to function as regulators remain poorly understood. Our recently solved crystal structure of CspC revealed that its pseudoactive site residues align closely with the catalytic triad of CspB, suggesting that it might be possible to ‘resurrect' the ancestral protease activity of the CspC and CspA pseudoproteases. Here, we demonstrate that restoring the catalytic triad to these pseudoproteases fails to resurrect their protease activity. We further show that the pseudoactive site substitutions differentially affect the stability and function of the CspC and CspA pseudoproteases: the substitutions destabilized CspC and impaired spore germination without affecting CspA stability or function. Thus, our results surprisingly reveal that the presence of a catalytic triad does not necessarily predict protease activity. Since homologs of C. difficile CspA occasionally carry an intact catalytic triad, our results indicate that bioinformatic predictions of enzyme activity may underestimate pseudoenzymes in rare cases.

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