Physiology/Pathology of T-Cell Intracellular Antigen 1-Like Protein: History
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T-cell intracellular antigen 1 (TIA1)-related/like (TIAR/TIAL1) protein is a multifunctional RNA-binding protein (RBP) involved in regulating many aspects of gene expression, independently or in combination with its paralog TIA1. TIAR was first described in 1992 by Paul Anderson’s lab in relation to the development of a cell death phenotype in immune system cells, as it possesses nucleolytic activity against cytotoxic lymphocyte target cells. Similar to TIA1, it is characterized by a subcellular nucleo-cytoplasmic localization and ubiquitous expression in the cells of different tissues of higher organisms.

  • TIAR
  • TIAL1
  • pathophysiology

1. Introduction

TIAR: One Gene, Two Main Isoforms and a Classical RBP Structure

T-cell intracellular antigen 1-related/like (TIAR/TIAL1) protein is a classical member of the RNA-binding protein (RBP) family. It was first identified in 1992 by Paul Anderson and colleagues [1], and was named TIA1-related or TIA1-like protein due to its high degree of identity and structural homology with its paralog TIA1—which had been identified one year earlier by the same group [2].
Since then, much effort has been directed towards studying and characterizing this gene and its products, including the different isoforms, its protein structure and organization, and its selective and specific interaction with RNA sequences. Likewise, its multiple functions in cellular processes and in pathology have been extensively investigated, as evidenced by the wealth of published information during the past three decades.
The human TIAR gene consists of 12 exons located on the chromosomal region 10q [3]. The correspondence between exons and the functional domains of the protein are as follows: exons 1–4 code for RNA-recognition motif/module 1 (RRM1), exons 5–7 for RRM2 and exons 8–10 for RRM3. Exon 11 and the most 5′ part of exon 12 encode the disorganized prion-like domain corresponding to the carboxyl terminus together with the 3′-untranslated region (3′-UTR) of its mature mRNA. Two major TIAR isoforms have been identified in vertebrates—TIARa (50 kDa) and TIARb (42 kDa)—which differ in 17 amino-acid peptides located between the ribonucleoprotein (RNP)1 and RNP2 motifs of RRM1. This additional peptide sequence in TIARa is the result of an alternative-splicing event in the last 51 nucleotides of exon 3 [3]. This extra peptide confers specificity to TIARa for the recognition of specific RNA sequences, as well as the potential for interaction with other proteins and/or post-translational modifications [4]. The exonic and intronic organization TIAR is conserved between mouse and human species and it is located in the 7F4 region of the murine genome [3]. Nowadays, there is little scientific evidence about the differential regulatory role between main TIAR isoforms (a and b); therefore, it will be an interesting challenge to be studied because characteristic patterns of TIAR isoforms could determine specific cellular interactome among proteins and/or RNAs with potential impacts on gene expression flux, biological processes and their pathophysiological consequences.

2. Inflammation

The functional roles of RBPs in immunity and its associated diseases are well known. The dysregulation of RBPs and their targets result in chronic inflammation and autoimmunity [26,46,55,152,153]. TIAR is a well-known attenuator of inflammation and, accordingly, it has been extensively studied as a key post-transcriptional regulator of inflammation and immune response. TIAR can collaboratively or competitively bind the same target mRNAs with other RBPs, such as AUF1, ELAVL1/HuR, KSRP, TIA1, TTP, Roquin or Regnase, to enhance or dampen regulatory activities [152,153]. These RBPs can also bind their own 3′-UTRs to negatively or positively regulate their expression. Both upstream signaling pathways and miRNA regulation shape the interactions between RBPs and target RNAs. In myeloid cells, TIAR has been shown to bind and regulate the translation and stability of various mRNA-encoding proteins important for inflammatory response, such as TNFα [45,55], Cox-2 [48,49], many proinflammatory cytokines [55], and IL-8 [154]. A study in macrophages using a combination of RNA-IP and microarray analysis (RIP-chip) identified over 400 mRNAs specifically bound by the full-length protein in response to endotoxin [98].
The dysregulation of RBPs results in chronic inflammation and autoimmunity. In this regard, a transcriptome meta-analysis identified an immune signature involving RBPs in the immune cells of patients with ulcerative colitis (UC), who showed significantly lower TIAR expression compared with healthy controls [103]. In the same study, the deletion of TIAR in macrophages using siRNAs resulted in an enhanced production of the inflammatory cytokine IL-1β [103]. By contrast the aberrant expression of TIA1 and TIAR has been documented in patients with rheumatic diseases, leading to the production of autoantibodies to TIA proteins, specifically, an increased prevalence in systemic lupus erythematosus and systemic sclerosis and correlations with clinical features [155].
Another noteworthy aspect is neutrophilic inflammation in asthma, which is associated with interleukin (IL)-17A, corticosteroid insensitivity and bronchodilator-induced forced expiratory volume in 1 s (FEV1) reversibility. IL-17A synergizes with TNF-α in the production of the neutrophil chemokine CXCL-8 by primary bronchial epithelial cells (PBECs). At the molecular level, epithelial hyper-responsiveness was associated with the failure of TIAR to translocate to the cytoplasm to halt CXCL-8 production, as confirmed by TIAR knockdown [156]. This is in line with the finding that hyper-responsive PBECs also produce enhanced levels of other inflammatory mediators. Normalizing the cytoplasmic translocation of TIAR is thus a potential therapeutic target in neutrophilic, corticosteroid-insensitive asthma [156].
TIAR has also been identified as a potential component of a gene signature linked to pulmonary sarcoidosis, as it was downregulated in patients with sarcoidosis compared with healthy individuals [157]. Nevertheless, further studies are required to evaluate the precise role for TIAR in inflammatory scenarios linked to human pathologies, such as autoimmunity, arthritis, ulcerative colitis, ulcerative colitis, asthma or pulmonary sarcoidosis.

3. Embryogenesis

The phenotypic differences observed between mice with the inactivation of TIAR [81] and/or TIA1 [46] indicate that they may cooperate or act independently during early embryogenesis. The phenotype of mice lacking TIAR appears to depend on the mouse strain in which the studies are performed. TIAR deficiency resulted in embryonic lethality in 100% of BALB/c mice, but only in 90% of C57BL/6 embryos. Crossing BALB/c TIAR +/− mice with C57BL/6 TIAR +/− mice produced 60% embryonic mortality. Of the remainder, half of the mice survived to adulthood but were sterile with abnormalities in spermatogenesis and oogenesis, as well as in the architecture of the gonads themselves. Other phenotypes included obesity, despite being born with lower body mass, and neurological disorders. In addition, the mice developed cervical cancer as adults [81]. Conversely, in a transgenic mouse model of TIAR overexpression, 77% of embryos had abnormalities at embryonic day 7.5 [90]. TIAR was also reported to control self-renewal and the attenuation of differentiation in mouse embryonic stem cells [97]. Overall, embryonic and germ cell development, as well as the differentiation of murine embryonic stem cells, are compromised by the reduction/absence or overexpression of TIAR [46,81,90,93,97,158]. In the case of the C. elegans, the TIA-1/TIAR homolog TIAR-1/TIAR-2 is required to induce germ cell apoptosis, and TIAR-1 protects female germ cells from heat shock [105,110,159].

4. Carcinogenesis

TIAR/TIAL1 has been studied in several transformed cells and solid tumors. The first seminal work showed that TIAR regulates translation of the c-myc oncogene mRNA in a 3′-UTR in K652 cells [56]. In the same vein, the knockdown of TIAR expression in HeLa improves cell proliferation [26,91]. By contrast, using a cellular gain-of-function model in HEK293 cells, TIAR overexpression was shown to inhibit cell proliferation and trigger apoptosis and autophagy/mitophagy, indicating that TIAR functions as a tumor suppressor in a p53-dependent manner [95]. TIAR was also identified as a transformation/tumor suppressor in lung cancer tumors in an shRNA library-based genome-wide loss-of-function screen [113]. These observations have been reinforced with recent findings revealing the role of TIAR as a tumor suppressor via interaction with the lncRNA MT1JP to modulate the p53 pathway [74]. Furthermore, the downregulated expression of TIAR has been observed in several cell lines and tumor samples [91,95,112,113,160] and it is an unfavorable prognostic marker in liver cancer [15] and osteosarcoma [161].
The genome-wide analysis of transcript variation in breast cancer identified TIAR as involved in aberrant splicing. Patterns of transcript variant expression identified “hub” genes that differentiated the cancerous and normal transcriptomes, and the dysregulated expression of alternative transcripts may reveal novel biomarkers for tumor development [162].
The silencing of TIA proteins in several tumor cell lines triggers the upregulation of HIF-1α expression, and rapid and severe hypoxia causes co-aggregation of TIA proteins, which suppress HIF-1α expression, reflecting the control of HIF-1α expression by TIAR/TIA1 [163].
A very recent study has demonstrated a tumor suppressor role for TIAR in the incidence/progression of skin squamous cell carcinoma (SSCC) [160]. The downregulation of muscleblind-like protein 1 (MBNL1) promoted cell metastases (measured as Transwell migration) in SCL-1 cells, whereas the upregulation of MBNL1 reduced cell metastasis. Additionally, the downregulation of MBNL1 suppressed the protein expression of TIAR, myogenic determinant 1 (MyoD1) and caspase-3 in vitro. Consistent with these observations, the inhibition of TIAR or MYOD1 expression attenuated the effects of MBNL1 in SSCC. These observations reveal that MBNL1 suppresses the cancer metastatic capacity of SSCC via by TIAL1/MYOD1/caspase-3 signaling pathways [160].
TIAR is also a negative regulator of the BRCA1 oncogene; it has been shown to block translation and reduce the protein expression of BRCA1 in chronic myeloid leukemia cells, which leads to aneuploidy, spindle toxin resistance and genomic instability [164]. TIAR-mediated repression of BRCA1 mRNA translation is responsible for the downregulation of BRCA1 protein level in BCR-ABL1-positive leukemia cells. This mechanism may contribute to genomic instability [164]. Moreover, it is plausible that TIAR has the same effect on BRCA1 protein expression in breast cancer [77,164]. As already mentioned, TIAR interacts with LOXL1-AS1 to modulate vasculogenic mimicry in glioma via the miR-374b-5p/MMP14 axis. This observation might reveal novel targets for glioma therapy [76].
Nonetheless, an oncogenic or tumor suppressor function for TIAR (and their isoforms) could be highly dependent on the cell-type and the associated interactomes involving both RNA-protein and protein–protein interactions and dynamics [8,21]. TIAR ablation in murine embryonic fibroblasts compromises cell proliferation by delaying cell cycle at G2/M phase and triggering adaptive autophagy [93]. Additionally, the knockdown of TIAR accelerates mitotic entry and leads to chromosomal instability in response to replication stress, in a manner that can be alleviated by the concomitant depletion of Cdc25B or inhibition of CDK1. As TIAR retains CDK1 in GMGs and attenuates CDK1 activity, it was proposed that the assembly of GMGs may represent a hitherto unrecognized mechanism that contributes to the activation of the G2/M checkpoint [104]. The depletion of both TIA1 and TIAL1 paralogs by CRISPR-Cas9 technology drives cell death after 7 days [38].
Tumor protein D52 (TPD52) reportedly plays an important role in the proliferation and metastasis of various cancer cells, including oral squamous cell carcinoma (OSCC), and it is expressed strongly at the hypoxic center of the tumor and is involved in cell death resistance. This occurred through a mechanism involving enhanced mRNA stability by binding of the mRNA to TIA1 and TIAR [165]. The simultaneous knockdown of TPD52 and HIF-1α significantly reduced cell viability. In addition, in vivo tumor-xenograft experiments showed that TPD52 acts as an autophagy inhibitor caused by a decrease in p62. Thus, the expression of TPD52 increases in OSCC cells under hypoxia in a HIF-independent manner and plays an important role in the proliferation and survival of the cells in concordance with HIF [165].
Recently, it has been shown that glycolysis and tumor immunity are inter-related cellular events in osteosarcoma that share glycolysis-immune-related genes. TIAR is one of these genes and a potential candidate to construct a gene signature risk score to predict the prognosis of patients with osteosarcoma [164].

5. Neurodegenerative Diseases

The timing, dosage and location of gene expression flux are the main determinants of brain architectural complexity. In neurons, this is achieved by specific sets of RBPs and their associated factors, which bind to specific cis-elements throughout the RNA sequence to regulate splicing, polyadenylation, stability, transport and localized translation at both axons and dendrites. Not surprisingly, the misregulation of RBP expression or disruption of their function due to mutations or sequestration into nuclear or cytoplasmic inclusions have been linked to the pathogenesis of several neuropsychiatric and neurodegenerative disorders, such as fragile-X syndrome, autism spectrum disorders, spinal muscular atrophy, amyotrophic lateral sclerosis and frontotemporal dementia. The roles of TIAR and other RBPs have been analyzed by their specific molecular and cellular functions, the neurological symptoms associated with their perturbation and their axo-dendritic transport/localization along with their target mRNAs as part of larger macromolecular complexes termed RNP granules [166].

5.1. Neurofibromatosis Type I

Neurofibromatosis type I (NF1) is a common inherited autosomal-dominant disease that affects 1 in 3500 individuals with mutations that promote the loss of function of the NF1 protein, neurofibromin, which is involved in diverse signaling cascades. The disease is completely penetrant, but shows variable phenotypic expression in patients. NF1 is a large gene, and its pre-mRNA undergoes alternative splicing [27]. One of the best characterized occupations 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 central nervous system neurons [27]. The isoform with the skipped exon 23a has 10-times greater Ras-GAP activity than the isoform, including exon 23a. This inclusion is tightly regulated by at least three different families of RBPs: CELF (CUG-BP, cytosine-uridine-guanine-binding protein) and ETR-3 (ELAV (embryonic lethal abnormal vision)-type RNA-binding protein-like factor) [167,168], Hu and TIA1 /TIAR. The CELF and Hu proteins promote exon 23a skipping, whereas the TIA1/TIAR proteins promote its inclusion [28,169]. The widespread clinical variability observed among patients cannot be explained by NF1 mutations alone and it is believed that modifier genes may have a role in the variability. The available information suggests that the regulation of alternative splicing may act as a modifier to contribute to the variable expression in NF1 [168].

5.2. Axon Regeneration

Axon regeneration is a coordinated and concerted process associated with various cellular events, including but not restricted to the injury sensing, axonal transport, synthesis of macromolecules, cellular energy homeostasis and cytoskeletal organization. Interestingly, a negative link between TIAR expression/post-translational modification and axon regeneration has been recently reported. Thus, C. elegans TIAR-2/TIAR protein functions cell autonomously to inhibit axon regeneration. TIAR-2 undergoes liquid–liquid phase separation in vitro and forms granules with liquid-like properties in vivo. Axon injury induces a transient increase in TIAR-2 granule number. The prion-like domain is necessary and sufficient for granule formation and for inhibiting regeneration. Tyrosine residues within the prion-like domain are important for granule formation and inhibition of regeneration. TIAR-2 is also serine phosphorylated in vivo. Non-phosphorylatable TIAR-2 variants do not form granules and are unable to inhibit axon regeneration. These observations suggest an in vivo function for phase-separated TIAR-2 and identify features critical for its function in axon regeneration [105]. However, there is a consensus that the regulation of a single terminal gene may not be sufficient to drive post-injury axon regeneration, especially across a long distance.

5.3. Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive and ultimately fatal neurocognitive disorder with behavioral disturbances characterized by brain neuron loss and deposition of misfolded proteins. Several studies have recently identified a new type of molecular pathology in AD that derives from the aggregation of RBPs, forming RNA–protein complexes that include SGs [170,171]. SGs progressively accumulate in the brains of transgenic models of tauopathy, and massively accumulate in patients with AD and other neurodegenerative diseases [170]. Some SGs (e.g., those positive for TIA1) co-localize with tau pathology, while other SGs (e.g., those positive for G3BP) often identify neurons that lack tau pathology. A significant increase in the expression of TIAR is found in the hippocampal area in AD, suggesting it could be linked with this process of neurodegeneration [83]. Further, the expression of TIAR is increased in neurons after ischemic cerebral injury [172]. However, many RBPs that are the core nucleating factors of SGs, including TIA1, TIAR, TTP and G3BP1, are also found in the pathological lesions of other neurological conditions, such as AD [94] and ischemic cerebral injury [172].

This entry is adapted from the peer-reviewed paper 10.3390/ijms23147836

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