TIA1 gene

The TIA1 gene (TIA1 stands for: T-cell-restricted intracellular antigen-1) is a protein-coding gene located on chromosome 2p13.3. An important paralog of this gene is TIAL1. Alternative splicing has been demonstrated for this gene, leading to different isoforms.

The product encoded by this gene, TIA-1, belongs to a family of RNA-binding proteins and has nucleolytic activity against cytotoxic lymphocytes (CTL). It has been suggested that this protein may be involved in the induction of apoptosis as it preferentially recognizes poly(A) homopolymers and induces DNA fragmentation in CTL targets. The major granule-associated species is a 15-kDa protein, which is thought to be derived by proteolytic cleavage from the carboxyl terminus of the 40-kDa product.

The RNA-binding protein involved in the regulation of alternative pre-RNA splicing and mRNA translation by binding to U-rich (uridine-rich) RNA sequences (Förch P et al. 2000). Binds to U-rich sequences immediately downstream of 5' splice sites in a uridine-rich small nuclear ribonucleoprotein (U snRNP)-dependent manner, thereby modulating alternative pre-RNA splicing (Dember LM et al. 1996).

Preferentially binds to the U-rich IAS1 sequence in a U1-snRNP-dependent manner; this binding is optimal when a 5' splice site is adjacent to IAS1. Activates the use of heterologous 5' splice sites; activation depends on the intron sequence downstream of the 5' splice site, with a preference for a downstream U-rich sequence. By interacting with SNRPC/U1-C, it promotes the recruitment and binding of spliceosomal U1 snRNP to 5' splice sites followed by U-rich sequences, facilitating atypical recognition of 5' splice sites by U1 snRNP (Izquierdo JM et al. 2007). Acts as a modulator of alternative splicing for the apoptotic FAS receptor, thereby promoting apoptosis. Binds to the 5' splice site region of FAS intron 5 to promote the accumulation of transcripts containing exon 6 at the expense of transcripts skipping exon 6, resulting in the transcription of a membrane-bound apoptotic FAS receptor that promotes apoptosis (Tian Q et al. 1991). Also binds to the corresponding AT-rich element in the genomic DNA of COL2A1 and may thereby be involved in the regulation of transcription. The encoded portein is involved in the repression of mRNA translation by binding to AU-rich elements (AREs) located in the 3'-untranslated regions (3' UTRs) of mRNA, including the target ARE-carrying mRNAs encoding TNF and PTGS2 (By similarity). Also participates in the cellular response to environmental stress by acting downstream of stress-induced phosphorylation of EIF2S1/EIF2A to promote recruitment of untranslated mRNAs to cytoplasmic stress granules (SGs), leading to stress-induced translational arrest. Possesses nucleolytic activity against cytotoxic lymphocyte target cells (Tian Q et al. 1991).

Diseases associated with TIA1 include:

• Welander myopathy
• Amyotrophic lateral sclerosis 26 with or without frontotemporal dementia.

1. Dember LM et al. (1996) Individual RNA recognition motifs of TIA-1 and TIAR have different RNA binding specificities. J Biol Chem 271:2783-2788.
2. Förch P et al. (2000) The apoptosis-promoting factor TIA-1 is a regulator of alternative pre-mRNA splicing. Mol Cell 6:1089-98.
3. Izquierdo JM et al. (2007) Two isoforms of the T-cell intracellular antigen 1 (TIA-1) splicing factor display distinct splicing regulation activities. Control of TIA-1 isoform ratio by TIA-1-related protein. J Biol Chem 282):19410-19417.
4. Tian Q et al. (1991) A polyadenylate binding protein localized to the granules of cytolytic lymphocytes induces DNA fragmentation in target cells. Cell 67:629-39.