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15 pages, 2615 KiB

Open AccessArticle

In Situ Peroxidase Labeling Followed by Mass-Spectrometry Reveals TIA1 Interactome

by Olga Gourdomichali, Katerina Zonke, Fedon-Giasin Kattan, Manousos Makridakis, Georgia Kontostathi, Antonia Vlahou and Epaminondas Doxakis

Biology 2022, 11(2), 287; https://doi.org/10.3390/biology11020287 - 11 Feb 2022

Cited by 2 | Viewed by 3228

Abstract

TIA1 is a broadly expressed DNA/RNA binding protein that regulates multiple aspects of RNA metabolism. It is best known for its role in stress granule assembly during the cellular stress response. Three RNA recognition motifs mediate TIA1 functions along with a prion-like domain [...] Read more.

TIA1 is a broadly expressed DNA/RNA binding protein that regulates multiple aspects of RNA metabolism. It is best known for its role in stress granule assembly during the cellular stress response. Three RNA recognition motifs mediate TIA1 functions along with a prion-like domain that supports multivalent protein-protein interactions that are yet poorly characterized. Here, by fusing the enhanced ascorbate peroxidase 2 (APEX2) biotin-labeling enzyme to TIA1 combined with mass spectrometry, the proteins in the immediate vicinity of TIA1 were defined in situ. Eighty-six and 203 protein partners, mostly associated with ribonucleoprotein complexes, were identified in unstressed control and acute stress conditions, respectively. Remarkably, the repertoire of TIA1 protein partners was highly dissimilar between the two cellular states. Under unstressed control conditions, the biological processes associated with the TIA1 interactome were enriched for cytosolic ontologies related to mRNA metabolism, such as translation initiation, nucleocytoplasmic transport, and RNA catabolism, while the protein identities were primarily represented by RNA binding proteins, ribosomal subunits, and eicosanoid regulators. Under acute stress, TIA1-labeled partners displayed a broader subcellular distribution that included the chromosomes and mitochondria. The enriched biological processes included splicing, translation, and protein synthesis regulation, while the molecular function of the proteins was enriched for RNA binding activity, ribosomal subunits, DNA double-strand break repair, and amide metabolism. Altogether, these data highlight the TIA1 spatial environment with its different partners in diverse cellular states and pave the way to dissect TIA1 role in these processes. Full article

(This article belongs to the Special Issue RNA-Binding Proteins: Function, Dysfunction and Disease)

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16 pages, 2827 KiB

Open AccessArticle

HuD Regulates mRNA-circRNA-miRNA Networks in the Mouse Striatum Linked to Neuronal Development and Drug Addiction

by Michela Dell’Orco, Amir Elyaderani, Annika Vannan, Shobana Sekar, Gregory Powell, Winnie S. Liang, Janet L. Neisewander and Nora I. Perrone-Bizzozero

Biology 2021, 10(9), 939; https://doi.org/10.3390/biology10090939 - 20 Sep 2021

Cited by 9 | Viewed by 3643

Abstract

The RNA-binding protein HuD (a.k.a., ELAVL4) is involved in neuronal development and synaptic plasticity mechanisms, including addiction-related processes such as cocaine conditioned-place preference (CPP) and food reward. The most studied function of this protein is mRNA stabilization; however, we have recently shown that [...] Read more.

The RNA-binding protein HuD (a.k.a., ELAVL4) is involved in neuronal development and synaptic plasticity mechanisms, including addiction-related processes such as cocaine conditioned-place preference (CPP) and food reward. The most studied function of this protein is mRNA stabilization; however, we have recently shown that HuD also regulates the levels of circular RNAs (circRNAs) in neurons. To examine the role of HuD in the control of coding and non-coding RNA networks associated with substance use, we identified sets of differentially expressed mRNAs, circRNAs and miRNAs in the striatum of HuD knockout (KO) mice. Our findings indicate that significantly downregulated mRNAs are enriched in biological pathways related to cell morphology and behavior. Furthermore, deletion of HuD altered the levels of 15 miRNAs associated with drug seeking. Using these sets of data, we predicted that a large number of upregulated miRNAs form competing endogenous RNA (ceRNA) networks with circRNAs and mRNAs associated with the neuronal development and synaptic plasticity proteins LSAMP and MARK3. Additionally, several downregulated miRNAs form ceRNA networks with mRNAs and circRNAs from MEF2D, PIK3R3, PTRPM and other neuronal proteins. Together, our results indicate that HuD regulates ceRNA networks controlling the levels of mRNAs associated with neuronal differentiation and synaptic physiology. Full article

(This article belongs to the Special Issue RNA-Binding Proteins: Function, Dysfunction and Disease)

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40 pages, 5605 KiB

Open AccessReview

hnRNP A/B Proteins: An Encyclopedic Assessment of Their Roles in Homeostasis and Disease

by Patricia A. Thibault, Aravindhan Ganesan, Subha Kalyaanamoorthy, Joseph-Patrick W. E. Clarke, Hannah E. Salapa and Michael C. Levin

Biology 2021, 10(8), 712; https://doi.org/10.3390/biology10080712 - 24 Jul 2021

Cited by 26 | Viewed by 6288

Abstract

The hnRNP A/B family of proteins is canonically central to cellular RNA metabolism, but due to their highly conserved nature, the functional differences between hnRNP A1, A2/B1, A0, and A3 are often overlooked. In this review, we explore and identify the shared and [...] Read more.

The hnRNP A/B family of proteins is canonically central to cellular RNA metabolism, but due to their highly conserved nature, the functional differences between hnRNP A1, A2/B1, A0, and A3 are often overlooked. In this review, we explore and identify the shared and disparate homeostatic and disease-related functions of the hnRNP A/B family proteins, highlighting areas where the proteins have not been clearly differentiated. Herein, we provide a comprehensive assembly of the literature on these proteins. We find that there are critical gaps in our grasp of A/B proteins’ alternative splice isoforms, structures, regulation, and tissue and cell-type-specific functions, and propose that future mechanistic research integrating multiple A/B proteins will significantly improve our understanding of how this essential protein family contributes to cell homeostasis and disease. Full article

(This article belongs to the Special Issue RNA-Binding Proteins: Function, Dysfunction and Disease)

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21 pages, 1844 KiB

Open AccessReview

An “Omic” Overview of Fragile X Syndrome

by Olivier Dionne and François Corbin

Biology 2021, 10(5), 433; https://doi.org/10.3390/biology10050433 - 13 May 2021

Cited by 15 | Viewed by 7926

Abstract

Fragile X syndrome (FXS) is a neurodevelopmental disorder associated with a wide range of cognitive, behavioral and medical problems. It arises from the silencing of the fragile X mental retardation 1 (FMR1) gene and, consequently, in the absence of its encoded protein, FMRP [...] Read more.

Fragile X syndrome (FXS) is a neurodevelopmental disorder associated with a wide range of cognitive, behavioral and medical problems. It arises from the silencing of the fragile X mental retardation 1 (FMR1) gene and, consequently, in the absence of its encoded protein, FMRP (fragile X mental retardation protein). FMRP is a ubiquitously expressed and multifunctional RNA-binding protein, primarily considered as a translational regulator. Pre-clinical studies of the past two decades have therefore focused on this function to relate FMRP’s absence to the molecular mechanisms underlying FXS physiopathology. Based on these data, successful pharmacological strategies were developed to rescue fragile X phenotype in animal models. Unfortunately, these results did not translate into humans as clinical trials using same therapeutic approaches did not reach the expected outcomes. These failures highlight the need to put into perspective the different functions of FMRP in order to get a more comprehensive understanding of FXS pathophysiology. This work presents a review of FMRP’s involvement on noteworthy molecular mechanisms that may ultimately contribute to various biochemical alterations composing the fragile X phenotype. Full article

(This article belongs to the Special Issue RNA-Binding Proteins: Function, Dysfunction and Disease)

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14 pages, 835 KiB

Open AccessReview

Oncogenic Potential of the Dual-Function Protein MEX3A

by Marcell Lederer, Simon Müller, Markus Glaß, Nadine Bley, Christian Ihling, Andrea Sinz and Stefan Hüttelmaier

Biology 2021, 10(5), 415; https://doi.org/10.3390/biology10050415 - 7 May 2021

Cited by 14 | Viewed by 4014

Abstract

MEX3A belongs to the MEX3 (Muscle EXcess) protein family consisting of four members (MEX3A-D) in humans. Characteristic for MEX3 proteins is their domain structure with 2 HNRNPK homology (KH) domains mediating RNA binding and a C-terminal really interesting new gene (RING) domain that [...] Read more.

MEX3A belongs to the MEX3 (Muscle EXcess) protein family consisting of four members (MEX3A-D) in humans. Characteristic for MEX3 proteins is their domain structure with 2 HNRNPK homology (KH) domains mediating RNA binding and a C-terminal really interesting new gene (RING) domain that harbors E3 ligase function. In agreement with their domain composition, MEX3 proteins were reported to modulate both RNA fate and protein ubiquitination. MEX3 paralogs exhibit an oncofetal expression pattern, they are severely downregulated postnatally, and re-expression is observed in various malignancies. Enforced expression of MEX3 proteins in various cancers correlates with poor prognosis, emphasizing their oncogenic potential. The latter is supported by MEX3A’s impact on proliferation, self-renewal as well as migration of tumor cells in vitro and tumor growth in xenograft studies. Full article

(This article belongs to the Special Issue RNA-Binding Proteins: Function, Dysfunction and Disease)

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16 pages, 1634 KiB

Open AccessReview

Musashi–1—A Stemness RBP for Cancer Therapy?

by Nadine Bley, Ali Hmedat, Simon Müller, Robin Rolnik, Alexander Rausch, Marcell Lederer and Stefan Hüttelmaier

Biology 2021, 10(5), 407; https://doi.org/10.3390/biology10050407 - 5 May 2021

Cited by 16 | Viewed by 4808

Abstract

The RNA–binding protein Musashi–1 (MSI1) promotes stemness during development and cancer. By controlling target mRNA turnover and translation, MSI1 is implicated in the regulation of cancer hallmarks such as cell cycle or Notch signaling. Thereby, the protein enhanced cancer growth and therapy resistance [...] Read more.

The RNA–binding protein Musashi–1 (MSI1) promotes stemness during development and cancer. By controlling target mRNA turnover and translation, MSI1 is implicated in the regulation of cancer hallmarks such as cell cycle or Notch signaling. Thereby, the protein enhanced cancer growth and therapy resistance to standard regimes. Due to its specific expression pattern and diverse functions, MSI1 represents an interesting target for cancer therapy in the future. In this review we summarize previous findings on MSI1′s implications in developmental processes of other organisms. We revisit MSI1′s expression in a set of solid cancers, describe mechanistic details and implications in MSI1 associated cancer hallmark pathways and highlight current research in drug development identifying the first MSI1–directed inhibitors with anti–tumor activity. Full article

(This article belongs to the Special Issue RNA-Binding Proteins: Function, Dysfunction and Disease)

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13 pages, 917 KiB

Open AccessReview

RNA-Binding Proteins Hold Key Roles in Function, Dysfunction, and Disease

by Sophia Kelaini, Celine Chan, Victoria A Cornelius and Andriana Margariti

Biology 2021, 10(5), 366; https://doi.org/10.3390/biology10050366 - 24 Apr 2021

Cited by 43 | Viewed by 12237

Abstract

RNA-binding proteins (RBPs) are multi-faceted proteins in the regulation of RNA or its RNA splicing, localisation, stability, and translation. Amassing proof from many recent and dedicated studies reinforces the perception of RBPs exerting control through differing expression levels, cellular localization and post-transcriptional alterations. [...] Read more.

RNA-binding proteins (RBPs) are multi-faceted proteins in the regulation of RNA or its RNA splicing, localisation, stability, and translation. Amassing proof from many recent and dedicated studies reinforces the perception of RBPs exerting control through differing expression levels, cellular localization and post-transcriptional alterations. However, since the regulation of RBPs is reliant on the micro-environment and events like stress response and metabolism, their binding affinities and the resulting RNA-RBP networks may be affected. Therefore, any misregulation and disruption in the features of RNA and its related homeostasis can lead to a number of diseases that include diabetes, cardiovascular disease, and other disorders such as cancer and neurodegenerative diseases. As such, correct regulation of RNA and RBPs is crucial to good health as the effect RBPs exert through loss of function can cause pathogenesis. In this review, we will discuss the significance of RBPs and their typical function and how this can be disrupted in disease. Full article

(This article belongs to the Special Issue RNA-Binding Proteins: Function, Dysfunction and Disease)

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15 pages, 600 KiB

Open AccessReview

RNA–Binding Protein HuD as a Versatile Factor in Neuronal and Non–Neuronal Systems

by Myeongwoo Jung and Eun Kyung Lee

Biology 2021, 10(5), 361; https://doi.org/10.3390/biology10050361 - 23 Apr 2021

Cited by 24 | Viewed by 3965

Abstract

HuD (also known as ELAVL4) is an RNA–binding protein belonging to the human antigen (Hu) family that regulates stability, translation, splicing, and adenylation of target mRNAs. Unlike ubiquitously distributed HuR, HuD is only expressed in certain types of tissues, mainly in neuronal systems. [...] Read more.

HuD (also known as ELAVL4) is an RNA–binding protein belonging to the human antigen (Hu) family that regulates stability, translation, splicing, and adenylation of target mRNAs. Unlike ubiquitously distributed HuR, HuD is only expressed in certain types of tissues, mainly in neuronal systems. Numerous studies have shown that HuD plays essential roles in neuronal development, differentiation, neurogenesis, dendritic maturation, neural plasticity, and synaptic transmission by regulating the metabolism of target mRNAs. However, growing evidence suggests that HuD also functions as a pivotal regulator of gene expression in non–neuronal systems and its malfunction is implicated in disease pathogenesis. Comprehensive knowledge of HuD expression, abundance, molecular targets, and regulatory mechanisms will broaden our understanding of its role as a versatile regulator of gene expression, thus enabling novel treatments for diseases with aberrant HuD expression. This review focuses on recent advances investigating the emerging role of HuD, its molecular mechanisms of target gene regulation, and its disease relevance in both neuronal and non–neuronal systems. Full article

(This article belongs to the Special Issue RNA-Binding Proteins: Function, Dysfunction and Disease)

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12 pages, 854 KiB

Open AccessReview

Role of Tristetraprolin in the Resolution of Inflammation

by Peter Rappl, Bernhard Brüne and Tobias Schmid

Biology 2021, 10(1), 66; https://doi.org/10.3390/biology10010066 - 19 Jan 2021

Cited by 18 | Viewed by 4980

Abstract

Inflammation is a crucial part of immune responses towards invading pathogens or tissue damage. While inflammatory reactions are aimed at removing the triggering stimulus, it is important that these processes are terminated in a coordinate manner to prevent excessive tissue damage due to [...] Read more.

Inflammation is a crucial part of immune responses towards invading pathogens or tissue damage. While inflammatory reactions are aimed at removing the triggering stimulus, it is important that these processes are terminated in a coordinate manner to prevent excessive tissue damage due to the highly reactive inflammatory environment. Initiation of inflammatory responses was proposed to be regulated predominantly at a transcriptional level, whereas post-transcriptional modes of regulation appear to be crucial for resolution of inflammation. The RNA-binding protein tristetraprolin (TTP) interacts with AU-rich elements in the 3′ untranslated region of mRNAs, recruits deadenylase complexes and thereby facilitates degradation of its targets. As TTP regulates the mRNA stability of numerous inflammatory mediators, it was put forward as a crucial post-transcriptional regulator of inflammation. Here, we summarize the current understanding of the function of TTP with a specific focus on its role in adding to resolution of inflammation. Full article

(This article belongs to the Special Issue RNA-Binding Proteins: Function, Dysfunction and Disease)

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