{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T22:43:52Z","timestamp":1784673832281,"version":"3.55.0"},"reference-count":45,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,3,4]],"date-time":"2022-03-04T00:00:00Z","timestamp":1646352000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"This work was supported by a grant from Ministerio de Ciencia e Innovaci\u00f3n and Agencia Espa\u00f1ola de Investigaci\u00f3n through FEDER funds (RTI2018-098517-B100) (MICINN\/AEI\/FEDER, UE). The CBMSO receives an institutional grant from Fundaci\u00f3n Ram\u00f3n Areces and Ba","award":["RTI2018-098517-B100 (MICINN\/AEI\/FEDER, UE)"],"award-info":[{"award-number":["RTI2018-098517-B100 (MICINN\/AEI\/FEDER, UE)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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\u2014in which the amino acid mutated in WDM and the adjacent ones were replaced by lysines, glutamic acids, or alanines\u2014allowed 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.<\/jats:p>","DOI":"10.3390\/cells11050884","type":"journal-article","created":{"date-parts":[[2022,3,6]],"date-time":"2022-03-06T20:35:50Z","timestamp":1646598950000},"page":"884","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Dynamics of T-Cell Intracellular Antigen 1-Dependent Stress Granules in Proteostasis and Welander Distal Myopathy under Oxidative Stress"],"prefix":"10.3390","volume":"11","author":[{"given":"Andrea","family":"Fern\u00e1ndez-G\u00f3mez","sequence":"first","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa, Consejo Superior de Investigaciones Cient\u00edficas, Universidad Aut\u00f3noma de Madrid (CSIC\/UAM), C\/Nicol\u00e1s Cabrera 1, Campus de Cantoblanco, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Velasco","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa, Consejo Superior de Investigaciones Cient\u00edficas, Universidad Aut\u00f3noma de Madrid (CSIC\/UAM), C\/Nicol\u00e1s Cabrera 1, Campus de Cantoblanco, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7942-4046","authenticated-orcid":false,"given":"Jos\u00e9","family":"Izquierdo","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa, Consejo Superior de Investigaciones Cient\u00edficas, Universidad Aut\u00f3noma de Madrid (CSIC\/UAM), C\/Nicol\u00e1s Cabrera 1, Campus de Cantoblanco, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/0092-8674(91)90536-8","article-title":"A polyadenylate binding protein localized to the granules of cytolytic lymphocytes induces DNA fragmentation in target cells","volume":"67","author":"Tian","year":"1991","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4937","DOI":"10.4049\/jimmunol.152.10.4937","article-title":"Intron-exon organization and chromosomal localization of the human TIA-1 gene","volume":"152","author":"Kawakami","year":"1994","journal-title":"J. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3829","DOI":"10.1093\/nar\/24.19.3829","article-title":"Structure, tissue distribution and genomic organization of the murine RRM-type RNA binding proteins TIA-1 and TIAR","volume":"24","author":"Beck","year":"1996","journal-title":"Nucleic Acids Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"19410","DOI":"10.1074\/jbc.M700688200","article-title":"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","volume":"282","author":"Izquierdo","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9520","DOI":"10.1128\/MCB.25.21.9520-9531.2005","article-title":"Identification and functional outcome of mRNAs associated with RNA-binding protein TIA-1","volume":"25","author":"Martindale","year":"2005","journal-title":"Mol. Cell Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2033","DOI":"10.1080\/15384101.2015.1053668","article-title":"T-cell intracellular antigens in health and disease","volume":"14","author":"Izquierdo","year":"2015","journal-title":"Cell Cycle"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1016\/j.molcel.2007.05.036","article-title":"SR proteins function in coupling RNAP II transcription to pre-mRNA splicing","volume":"26","author":"Das","year":"2007","journal-title":"Mol. Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6287","DOI":"10.1128\/MCB.20.17.6287-6299.2000","article-title":"The RNA-binding protein TIA-1 is a novel mammalian splicing regulator acting through intron sequences adjacent to a 5\u2032 splice site","volume":"20","author":"Bourgeois","year":"2000","journal-title":"Mol. Cell. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6882","DOI":"10.1093\/emboj\/cdf668","article-title":"The splicing regulator TIA-1 interacts with U1-C to promote U1 snRNP recruitment to 5\u2032 splice sites","volume":"21","author":"Puig","year":"2002","journal-title":"EMBO J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1016\/S1097-2765(00)00107-6","article-title":"The apoptosis-promoting factor TIA-1 is a regulator of alternative pre-mRNA splicing","volume":"6","author":"Puig","year":"2000","journal-title":"Mol. Cell"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Wang, Z., Kayikci, M., Briese, M., Zarnack, K., Luscombe, N.M., Rot, G., Zupan, B., Curk, T., and Ule, J. (2010). iCLIP predicts the dual splicing effects of TIA-RNA interactions. PLoS Biol., 8.","DOI":"10.1371\/journal.pbio.1000530"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1016\/j.molcel.2018.01.011","article-title":"The TIA1 RNA-binding protein family regulates EIF2AK2-mediated stress response and cell cycle progression","volume":"69","author":"Meyer","year":"2018","journal-title":"Mol. Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1038\/s41586-020-2077-3","article-title":"A large-scale binding and functional map of human RNA-binding proteins","volume":"583","author":"Freese","year":"2020","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1083\/jcb.147.7.1431","article-title":"RNA-binding proteins TIA-1 and TIAR link the phosphorylation of eIF-2\u03b1 to the assembly of mammalian stress granules","volume":"147","author":"Kedersha","year":"1999","journal-title":"J. Cell. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1083\/jcb.151.6.1257","article-title":"Dynamic shuttling of TIA-1 accompanies the recruitment of mRNA to mammalian stress granules","volume":"151","author":"Kedersha","year":"2000","journal-title":"J. Cell. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1091\/mbc.01-05-0221","article-title":"Evidence that ternary complex (eIF2-GTP-tRNA(i)(Met))-deficient preinitiation complexes are core constituents of mammalian stress granules","volume":"13","author":"Kedersha","year":"2002","journal-title":"Mol. Cell. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"30070","DOI":"10.1074\/jbc.M706273200","article-title":"T-cell intracellular antigen-1 (TIA-1)-induced translational silencing promotes the decay of selected mRNAs","volume":"282","author":"Yamasaki","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4154","DOI":"10.1093\/emboj\/19.15.4154","article-title":"TIA-1 is a translational silencer that selectively regulates the expression of TNF-\u03b1","volume":"19","author":"Piecyk","year":"2000","journal-title":"EMBO J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/S0960-8966(98)00008-X","article-title":"Welander distal myopathy\u2014An overview","volume":"8","author":"Borg","year":"1998","journal-title":"Neuromuscul. Disord."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1002\/1531-8249(199909)46:3<399::AID-ANA16>3.0.CO;2-Q","article-title":"Genetic linkage of Welander distal myopathy to chromosome 2p13","volume":"46","author":"Borg","year":"1999","journal-title":"Ann. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1016\/S0960-8966(01)00338-8","article-title":"Welander distal myopathy outside the Swedish population: Phenotype and genotype","volume":"12","author":"Somer","year":"2002","journal-title":"Neuromuscul. Disord."},{"key":"ref_22","first-page":"1","article-title":"Myopathia distalis tarda hereditaria; 249 examined cases in 72 pedigrees","volume":"265","author":"Welander","year":"1951","journal-title":"Acta Med. Scand. Suppl."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1002\/ana.23831","article-title":"Welander distal myopathy is caused by a mutation in the RNA-binding protein TIA1","volume":"73","author":"Hackman","year":"2013","journal-title":"Ann. Neurol."},{"key":"ref_24","first-page":"572","article-title":"Welander distal myopathy caused by an ancient founder mutation in TIA1 associated with perturbed splicing","volume":"34","author":"Klar","year":"2013","journal-title":"Hum. Mutat."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e0029918","DOI":"10.1128\/MCB.00299-18","article-title":"A heterologous cell model for studying the role of T-cell intracellular antigen 1 in Welander distal myopathy","volume":"39","author":"Carrascoso","year":"2019","journal-title":"Mol. Cell. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1016\/j.tcb.2016.05.004","article-title":"Principles and properties of stress granules","volume":"26","author":"Protter","year":"2016","journal-title":"Trends Cell Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/j.cell.2015.12.038","article-title":"ATPase-modulated stress granules contain a diverse proteome and substructure","volume":"164","author":"Jain","year":"2016","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1016\/j.cell.2018.06.006","article-title":"A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins","volume":"174","author":"Wang","year":"2018","journal-title":"Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"31832","DOI":"10.1073\/pnas.2007423117","article-title":"Micellar TIA1 with folded RNA binding domains as a model for reversible stress granule formation","volume":"117","author":"Fritzsching","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e2014188118","DOI":"10.1073\/pnas.2014188118","article-title":"TIA1 potentiates tau phase separation and promotes generation of toxic oligomeric tau","volume":"118","author":"Ash","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5383","DOI":"10.1091\/mbc.e04-08-0715","article-title":"Stress granule assembly is mediated by prion-like aggregation of TIA-1","volume":"15","author":"Gilks","year":"2004","journal-title":"Mol. Biol. Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2403","DOI":"10.1093\/nar\/gkab080","article-title":"Tandem RNA binding sites induce self-association of the stress granule marker protein TIA-1","volume":"49","author":"Loughlin","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/j.cell.2013.07.038","article-title":"Altered ribostasis: RNA-protein granules in degenerative disorders","volume":"154","author":"Ramaswami","year":"2013","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4421","DOI":"10.1111\/bph.14790","article-title":"Stress granule: A promising target for cancer treatment","volume":"176","author":"Gao","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1016\/j.neuron.2017.07.025","article-title":"TIA1 mutations in amyotrophic lateral sclerosis and frontotemporal dementia promote phase separation and alter stress granule dynamics","volume":"95","author":"Mackenzie","year":"2017","journal-title":"Neuron"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/j.neuron.2013.07.033","article-title":"Converging mechanisms in als and FTD: Disrupted RNA and protein homeostasis","volume":"79","author":"Ling","year":"2013","journal-title":"Neuron"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1016\/j.celrep.2016.04.045","article-title":"Interaction of tau with the RNA-binding protein TIA1 regulates tau pathophysiology and toxicity","volume":"15","author":"Vanderweyde","year":"2016","journal-title":"Cell Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5153","DOI":"10.1523\/JNEUROSCI.0783-09.2009","article-title":"Cross-seeding fibrillation of Q\/N-rich proteins offers new pathomechanism of polyglutamine diseases","volume":"29","author":"Furukawa","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e1669","DOI":"10.1038\/cddis.2015.43","article-title":"T-cell intracellular antigens function as tumor suppressor genes","volume":"6","author":"Izquierdo","year":"2015","journal-title":"Cell Death Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e00174-17","DOI":"10.1128\/MCB.00174-17","article-title":"T-cell intracellular antigens and Hu antigen R antagonistically modulate mitochondrial activity and dynamics by regulating optic atrophy 1 gene expression","volume":"37","author":"Carrascoso","year":"2017","journal-title":"Mol. Cell. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"6545","DOI":"10.1093\/nar\/17.16.6545","article-title":"A simple method for site-directed mutagenesis using the polymerase chain reaction","volume":"17","author":"Hemsley","year":"1989","journal-title":"Nucleic Acids Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"108705","DOI":"10.1016\/j.celrep.2021.108705","article-title":"Predicting protein condensate formation using machine learning","volume":"34","author":"Jansen","year":"2021","journal-title":"Cell Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1814","DOI":"10.1261\/rna.1684009","article-title":"Metazoan stress granule assembly is mediated by P-eIF2\u03b1-dependent and -independent mechanisms","volume":"15","author":"Farny","year":"2009","journal-title":"RNA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1016\/j.celrep.2015.05.043","article-title":"Structural and functional analysis of the GADD34: PP1 eIF2\u03b1 phosphatase","volume":"11","author":"Choy","year":"2015","journal-title":"Cell Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.cell.2018.12.035","article-title":"Considerations and challenges in studying liquid-liquid phase separation and biomolecular condensates","volume":"176","author":"Alberti","year":"2019","journal-title":"Cell"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/5\/884\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:31:54Z","timestamp":1760135514000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/5\/884"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,4]]},"references-count":45,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["cells11050884"],"URL":"https:\/\/doi.org\/10.3390\/cells11050884","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,4]]}}}