T-Cell Intracellular Antigens and Hu Antigen R Antagonistically Modulate Mitochondrial Activity and Dynamics by Regulating Optic Atrophy 1 Gene Expression

Abstract

Mitochondria undergo frequent morphological changes to control their function. We show here that T-cell intracellular antigens (TIA1b/TIARb) and Hu antigen R (HuR) have antagonistic roles in mitochondrial function by modulating the expression of mitochondrial shaping proteins. Expression of TIA1b/TIARb alters the mitochondrial dynamic network by enhancing fission and clustering, which is accompanied by a decrease in respiration. In contrast, HuR expression promotes fusion and cristae remodeling and increases respiratory activity. Mechanistically, TIA proteins downregulate the expression of optic atrophy 1 (OPA1) protein via switching of the splicing patterns of OPA1 to facilitate the production of OPA1 variant 5 (OPA1v5). Conversely, HuR enhances the expression of OPA1 mRNA isoforms through increasing steady-state levels and targeting translational efficiency at the 3= untranslated region. Knockdown of TIA1/ TIAR or HuR partially reversed the expression profile of OPA1, whereas knockdown of OPA1 or overexpression of OPA1v5 provoked mitochondrial clustering. Middle-term expression of TIA1b/TIARb triggers reactive oxygen species production and mitochondrial DNA damage, which is accompanied by mitophagy, autophagy, and apoptosis. In contrast, HuR expression promotes mitochondrion-dependent cell proliferation. Collectively, these results provide molecular insights into the antagonistic functions of TIA1b/TIARb and HuR in mitochondrial activity dynamics and suggest that their balance might contribute to mitochondrial physiopathology.

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

“…An empty vector (GFP) was used as a negative control, and a vector coexpressing GFP and the RNA-binding protein HuR (human R antigen) was used in some experiments as an additional control ( Fig. 1D) (24,25). We used these cell lines to investigate the three specific regulatory aspects of TIA1 in WDM, namely, regulation of exon 7 splicing in SMN2; the formation, assembly, and/or disassembly of SGs; and effects on mitochondrial dynamics and function (e.g., autophagy, mitophagy, and apoptosis).…”

“…GFP (control)-and TIA1-expressing FT293 cells were transiently transfected with SMN1/SMN2 and NF1 minigenes for 24 h. Western blots of GFP-tagged fusion proteins upon tetracycline treatment for 24 h are shown. Analysis of alternative splicing was carried out using RT-PCR assays as described previously (25,44,45). (C to E) Analysis of ectopic SMN1/SMN2 and NF1 alternative splicing in HEK293 (C), SH-SY5Y (D), and C2C12 (E) cells cotransfected with the corresponding minigenes and expression plasmids.…”

“…Mitochondria are essential for these functions and strongly contribute to the cellular redox state (47). We recently demonstrated that short-term TIA1b overexpression in FT293 cells drives mitochondrial remodeling, involving mitochondrial clustering, fission, and, ultimately, dysfunction (25). We thus evaluated mitochondrial dynamics in uninduced FT293 cells and WDM-and WT-TIA1-expressing FT293 cells.…”

“…Consequently, TIA1 targets the cellular and molecular biology of RNAs and proteins, determining their fate in ribonucleoprotein (RNP) complexes (15)(16)(17)(18)(19)(20). TIA1 impacts genes involved in main biological programs such as embryonic development, cell survival and death, differentiation, stress responses, inflammation, virus infection, and oncogenesis, all of which are important in physiopathology (11,(15)(16)(17)(18)(19)(20)(23)(24)(25). Targeted ablation of TIA1 results in embryonic lethality (26,27), demonstrating its importance in early development, but the penetrance varies between TIA proteins: around 50% in mice lacking TIA1 (26,27) and close to 100% in TIAR knockout mice (28).…”

Genetic Perturbation of TIA1 Reveals a Physiological Role in Fear Memory

“…In addition, TIA1 represses translation of target mRNAs containing adenineand uridine-rich elements (AREs) in the 3 0 UTR (Anderson and Kedersha, 2002;Dixon et al, 2003). At the cellular level, TIA1 regulates lipid storage and membrane dynamics (Heck et al, 2014), recruitment of the protein synthesis machinery to the tubulin cytoskeleton (Li et al, 2014), cell cycle progression (Meyer et al, 2018; Sá nchez-Jimé nez and Izquierdo, 2013), and mitochondrial function (Carrascoso et al, 2017;Tak et al, 2017). Furthermore, these functions of TIA1 are not necessarily intertwined with its role as a component in stress granules during exogenously applied stress.…”