mRNA turnover is the process by which an mRNA is degraded before or after translation. This can occur at the 5′ end of the mRNA through decapping by the activity of DCP1 and DCP2 (dipeptidyl carboxypeptidase 1 and 2) and the exonuclease XRN1 (5′-3′ exoribonuclease 1)
[56][71] or at the 3′ end, mediated by the exosome, resulting in deadenylation of the poly(A) tail and recruitment of exonucleases
[57][72]. The mRNA regions involved are the ARE sequences located in the 3′-UTR that favor the binding of TIA1, AUF1 (AU-rich element RNA-binding protein 1), KRSP and TTP, which recruit proteins involved in the degradation process. Binding of TIA1 to these regions favors both mRNA deadenylation and stimulation of 5′cap removal, in a cell-specific and stress-independent manner
[19][35]. By contrast, proteins such as HuR stabilize mRNA, likely because of their inability to recruit the exosome to ARE sequences
[58][73] (
Figure 3). mRNA stability can also be regulated through the binding of microRNAs (miRNAs), which can trigger degradation. miRNAs are small fragments of non-coding RNA, of 19–24 nucleotides, that regulate gene expression by pairing with sequences typically located in the 3′ UTR regions of mRNAs. The interaction of miRNA with RNA stimulates the recruitment of the RISC complex (RNA-induced silencing complex) and mRNA cleavage. Several studies suggest that 20–30% of gene expression is controlled by miRNAs
[59][74]. A large-scale expression-platform study demonstrated that transient knockdown of TIA1 and TIAR in HeLa cells resulted in the overexpression of 29 miRNAs
[60][75]. This result was interpreted as a strategy to counteract the differential expression and cellular phenotypes associated with the downregulation of TIA proteins
[60][75]. Moreover, in cellular microvesicles abundantly expressing TIA1 and representing a mechanism of cellular communication in stem cells, 365 miRNAs were identified, the target mRNAs of which are related to organism development, survival and differentiation, as well as regulation of the immune response
[61][76]. This evidence suggests that TIA1 can activate or repress the transcription of miRNAs through a mechanism that is currently unknown and can interact with them to modulate gene expression. Finally, it is worth noting that non-coding RNAs have been identified, both small RNAs and long, non-coding RNAs, that repress TIA1-associated expression through direct interaction with its mRNA, impacting its translation and/or stability (e.g., miR-19a
[62][77], miR-487a
[63][78], mivaRNAI-138
[64][79]) or the direct sequestration of TIA1 and other RNAs through a molecular sponge mechanism (e.g., FLJ11812)
[65][80], NORAD
[66][81], MALAT1
[67][82]).
Figure 3. Timeline and milestones of TIA1 research. Milestones in the study of TIA1/TIA-1 found in PubMed/MEDLINE database. The references to build this figure are the following:
[1][2][3][4][5][6][21][16][68][7][11][14][17][18][19][20][22][23][25][27][29][31][58][62][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][1,2,3,4,5,6,13,19,20,21,24,31,33,34,35,36,37,38,40,42,44,46,73,77,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114].