scholarly journals A Heterologous Cell Model for Studying the Role of T-Cell Intracellular Antigen 1 in Welander Distal Myopathy

2018 ◽  
Vol 39 (1) ◽  
Author(s):  
Isabel Carrascoso ◽  
Carmen Sánchez-Jiménez ◽  
Elena Silion ◽  
José Alcalde ◽  
José M. Izquierdo
Keyword(s):  
T Cell ◽  
Rna Binding ◽  
Cell Model ◽  
Ectopic Expression ◽  
Cell Phenotype ◽  
Distal Myopathy ◽  
Granule Formation ◽  
Intracellular Antigen ◽  
Hands And Feet ◽  
Heterologous Cell

ABSTRACT Welander distal myopathy (WDM) is a muscle dystrophy characterized by adult-onset distal muscle weakness, prevalently impacting the distal long extensors of the hands and feet. WDM is an autosomal dominant disorder caused by a missense mutation (c.1362G>A; p.E384K) in the TIA1 (T-cell intracellular antigen 1) gene, which encodes an RNA-binding protein basically required for the posttranscriptional regulation of RNAs. We have developed a heterologous cell model of WDM to study the molecular and cellular events associated with mutated TIA1 expression. Specifically, we analyzed how this mutation affects three regulatory functions mediated by TIA1: (i) control of alternative SMN2 (survival motor neuron 2) splicing; (ii) formation, assembly, and disassembly of stress granules; and (iii) mitochondrial dynamics and its consequences for mitophagy, autophagy, and apoptosis. Our results show that whereas WDM-associated TIA1 expression had only a mild effect on SMN2 splicing, it led to suboptimal adaptation to environmental stress, with exacerbated stress granule formation that was accompanied by mitochondrial dysfunction and autophagy. Overall, our observations indicate that some aspects of the cell phenotype seen in muscle of patients with WDM can be recapitulated by ectopic expression of WDM-TIA1 in embryonic kidney cells, highlighting the potential of this model to investigate the pathogenesis of this degenerative disease and possible therapeutics.

scholarly journals Deficiency of T-Cell Intracellular Antigen 1 in Murine Embryonic Fibroblasts Is Associated with Changes in Mitochondrial Morphology and Respiration

2021 ◽  
Vol 22 (23) ◽  
pp. 12775
Author(s):  
Isabel Carrascoso ◽  
Beatriz Ramos Velasco ◽  
José M. Izquierdo
Keyword(s):  
T Cell ◽  
Rna Binding ◽  
Mitochondrial Dynamics ◽  
Rna Binding Protein ◽  
Mitochondrial Morphology ◽  
Embryonic Fibroblasts ◽  
Intracellular Antigen ◽  
Molecular Components ◽  
Shed Light

T-cell intracellular antigen 1 (TIA1) is a multifunctional RNA-binding protein involved in regulating gene expression and splicing during development and in response to environmental stress, to maintain cell homeostasis and promote survival. Herein, we used TIA1-deficient murine embryonic fibroblasts (MEFs) to study their role in mitochondria homeostasis. We found that the loss of TIA1 was associated with changes in mitochondrial morphology, promoting the appearance of elongated mitochondria with heterogeneous cristae density and size. The proteomic patterns of TIA1-deficient MEFs were consistent with expression changes in molecular components related to mitochondrial dynamics/organization and respiration. Bioenergetics analysis illustrated that TIA1 deficiency enhances mitochondrial respiration. Overall, our findings shed light on the role of TIA1 in mitochondrial dynamics and highlight a point of crosstalk between potential pro-survival and pro-senescence pathways.

Permissive roles of hematopoietin and cytokine tyrosine kinase receptors in early T-cell development

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 2083-2090 ◽  
Author(s):  
Christina T. Jensen ◽  
Charlotta Böiers ◽  
Shabnam Kharazi ◽  
Anna Lübking ◽  
Tobias Rydén ◽  
...  
Keyword(s):  
T Cell ◽  
Tyrosine Kinase ◽  
T Cell Development ◽  
Ectopic Expression ◽  
Cell Development ◽  
Cell Phenotype ◽  
Tyrosine Kinase Receptors ◽  
Adult Mice ◽  
T Lymphopoiesis

Although several cytokines have been demonstrated to be critical regulators of development of multiple blood cell lineages, it remains disputed to what degree they act through instructive or permissive mechanisms. Signaling through the FMS-like tyrosine kinase 3 (FLT3) receptor and the hematopoietin IL-7 receptor α (IL-7Rα) has been demonstrated to be of critical importance for sustained thymopoiesis. Signaling triggered by IL-7 and thymic stromal lymphopoietin (TSLP) is dependent on IL-7Rα, and both ligands have been implicated in T-cell development. However, we demonstrate that, whereas thymopoiesis is abolished in adult mice doubly deficient in IL-7 and FLT3 ligand (FLT3L), TSLP does not play a key role in IL-7–independent or FLT3L-independent T lymphopoiesis. Furthermore, whereas previous studies implicated that the role of other cytokine tyrosine kinase receptors in T lymphopoiesis might not involve permissive actions, we demonstrate that ectopic expression of BCL2 is sufficient not only to partially correct the T-cell phenotype of Flt3l−/− mice but also to rescue the virtually complete loss of all discernable stages of early T lymphopoiesis in Flt3l−/−Il7r−/− mice. These findings implicate a permissive role of cytokine receptors of the hematopoietin and tyrosine kinase families in early T lymphopoiesis.

scholarly journals Alternative splicing of the neurofibromatosis type I pre-mRNA

2011 ◽  
Vol 32 (2) ◽  
pp. 131-138 ◽  
Author(s):  
Victoria A. Barron ◽  
Hua Lou
Keyword(s):  
Alternative Splicing ◽  
T Cell ◽  
Rna Binding ◽  
Binding Protein ◽  
Phenotypic Expression ◽  
Neurofibromatosis Type ◽  
Type I ◽  
Neurofibromatosis Type I ◽  
Variable Expression ◽  
Intracellular Antigen

NF1 (neurofibromatosis type I) is a common genetic disease that affects one in 3500 individuals. The disease is completely penetrant but shows variable phenotypic expression in patients. NF1 is a large gene, and its pre-mRNA undergoes alternative splicing. The NF1 protein, neurofibromin, is involved in diverse signalling cascades. One of the best characterized functions of NF1 is its function as a Ras-GAP (GTPase-activating protein). NF1 exon 23a is an alternative exon that lies within the GAP-related domain of neurofibromin. This exon is predominantly included in most tissues, and it is skipped in CNS (central nervous system) neurons. The isoform in which exon 23a is skipped has 10 times higher Ras-GAP activity than the isoform in which exon 23a is included. Exon 23a inclusion is tightly regulated by at least three different families of RNA-binding proteins: CELF {CUG-BP (cytosine-uridine-guanine-binding protein) and ETR-3 [ELAV (embryonic lethal abnormal vision)-type RNA-binding protein]-like factor}, Hu and TIA-1 (T-cell intracellular antigen 1)/TIAR (T-cell intracellular antigen 1-related protein). The CELF and Hu proteins promote exon 23a skipping, while the TIA-1/TIAR proteins promote its inclusion. The widespread clinical variability that is observed among NF1 patients cannot be explained by NF1 mutations alone and it is believed that modifier genes may have a role in the variability. We suggest that the regulation of alternative splicing may act as a modifier to contribute to the variable expression in NF1 patients.

scholarly journals Chicken RNA-binding protein T-cell internal antigen-1 contributes to stress granule formation in chicken cells and tissues

2018 ◽  
Vol 19 (1) ◽  
pp. 3
Author(s):  
Yingjie Sun ◽  
Pin Zhang ◽  
Hang Zheng ◽  
Luna Dong ◽  
Lei Tan ◽  
...  
Keyword(s):  
T Cell ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Stress Granule ◽  
Granule Formation

scholarly journals RNA Binding of T-cell Intracellular Antigen-1 (TIA-1) C-terminal RNA Recognition Motif Is Modified by pH Conditions

2013 ◽  
Vol 288 (36) ◽  
pp. 25986-25994 ◽  
Author(s):  
Isabel Cruz-Gallardo ◽  
Ángeles Aroca ◽  
Cecilia Persson ◽  
B. Göran Karlsson ◽  
Irene Díaz-Moreno
Keyword(s):  
T Cell ◽  
Rna Binding ◽  
Rna Recognition Motif ◽  
Rna Recognition ◽  
Recognition Motif ◽  
Intracellular Antigen ◽  
Ph Conditions

scholarly journals SARS-CoV-2 Nucleocapsid protein attenuates stress granule formation and alters gene expression via direct interaction with host mRNAs

2020 ◽  
Author(s):  
Syed Nabeel-Shah ◽  
Hyunmin Lee ◽  
Nujhat Ahmed ◽  
Edyta Marcon ◽  
Shaghayegh Farhangmehr ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Binding ◽  
Antiviral Drug ◽  
Ectopic Expression ◽  
Stress Granule ◽  
Hek293 Cells ◽  
Physical Interaction ◽  
Granule Formation ◽  
N Protein ◽  
Target Mrnas

AbstractThe COVID-19 pandemic has caused over one million deaths thus far. There is an urgent need for the development of specific viral therapeutics and a vaccine. SARS-CoV-2 nucleocapsid (N) protein is highly expressed upon infection and is essential for viral replication, making it a promising target for both antiviral drug and vaccine development. Here, starting from a functional proteomics workflow, we initially catalogued the protein-protein interactions of 21 SARS-CoV-2 proteins in HEK293 cells, finding that the stress granule resident proteins G3BP1 and G3BP2 copurify with N with high specificity. We demonstrate that N protein expression in human cells sequesters G3BP1 and G3BP2 through its physical interaction with these proteins, attenuating stress granule (SG) formation. The ectopic expression of G3BP1 in N-expressing cells was sufficient to reverse this phenotype. Since N is an RNA-binding protein, we performed iCLIP-sequencing experiments in cells, with or without exposure to oxidative stress, to identify the host RNAs targeted by N. Our results indicate that SARS-CoV-2 N protein binds directly to thousands of mRNAs under both conditions. Like the G3BPs stress granule proteins, N was found to predominantly bind its target mRNAs in their 3’UTRs. RNA sequencing experiments indicated that expression of N results in wide-spread gene expression changes in both unstressed and oxidatively stressed cells. We suggest that N regulates host gene expression by both attenuating stress granules and binding directly to target mRNAs.

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