Dynamics of T-Cell Intracellular Antigen 1-Dependent Stress Granules in Proteostasis and Welander Distal Myopathy under Oxidative Stress.

Andrea Fernández-Gómez,Beatriz Ramos Velasco,José M Izquierdo

doi:10.3390/cells11050884

Abstract

T-cell intracellular antigen 1 (TIA1) is an RNA-binding protein that is primarily involved in the post-transcriptional regulation of cellular RNAs. Furthermore, it is a key component of stress granules (SGs), RNA, and protein aggregates that are formed in response to stressful stimuli to reduce cellular activity as a survival mechanism. TIA1 p.E384K mutation is the genetic cause of Welander distal myopathy (WDM), a late-onset muscular dystrophy whose pathogenesis has been related to modifying SG dynamics. In this study, we present the results obtained by analyzing two specific aspects: (i) SGs properties and dynamics depending on the amino acid at position 384 of TIA1; and (ii) the formation/disassembly time-course of TIA1WT/WDM-dependent SGs under oxidative stress. The generation of TIA1 variants—in which the amino acid mutated in WDM and the adjacent ones were replaced by lysines, glutamic acids, or alanines—allowed us to verify that the inclusion of a single lysine is necessary and sufficient to alter SGs dynamics. Moreover, time-lapse microscopy analysis allowed us to establish in vivo the dynamics of TIA1WT/WDM-dependent SG formation and disassembly, after the elimination of the oxidizing agent, for 1 and 3 h, respectively. Our observations show distinct dynamics between the formation and disassembly of TIA1WT/WDM-dependent SGs. Taken together, this study has allowed us to expand the existing knowledge on the role of TIA1 and the WDM mutation in SG formation.

Highlights

IntroductionT-cell intracellular antigen 1 (TIA1) is expressed in a cell- and tissue-dependent manner in the organism [3,4]
To further study the point mutation associated with Welander distal myopathy (WDM) and its role in the dynamics of stress granules (SG), variants of the protein T-cell intracellular antigen 1 (TIA1) were designed in which this amino acid and the two
To further study the point mutation associated with WDM and its role in the dynamof 17 ics of SGs, variants of the protein TIA1 were designed in which this amino acid and5 the two adjacent ones were replaced by triplets of lysines, glutamic acids, and alanines (TIA1aKKK, TIA1aEEE, and TIA1aAAA, respectively) in order to try to enhance the effect of this mutation

Summary

Introduction

TIA1 is expressed in a cell- and tissue-dependent manner in the organism [3,4] It is distributed between the nucleus and the cytoplasm, and plays an important role in the regulation of gene expression and RNA metabolism [5,6]. TIA1 can bind to translation initiation factors and to the small subunit of ribosomes, forming complexes that interact with mRNA and aggregate thanks to the C-terminal prion domain of TIA1, among others. These aggregates, called stress granules (SG), prevent the translation of some mRNAs, and favor the translation of those that give rise to proteins that help to overcome stress and recover homeostasis [14–16]. Other processes in which TIA1 participates are transport, subcellular localization, and mRNA stability [5,6,17,18]

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Conclusion