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Regulation of the Human PERK mRNA Translation by Upstream Open Reading Frames

2021-05-25Conference object Restricted access
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dc.contributor.authorFernandes, Rafael
dc.contributor.authorRodrigues, Rosário
dc.contributor.authorLopes, Pedro
dc.contributor.authorRomão, Luísa
dc.date.accessioned2022-07-09T15:17:27Z
dc.date.embargo2027-12-31
dc.date.issued2021-05-25
dc.description.abstractUpstream open reading frames (uORFs) are cis-acting elements located within the 5’ leader sequence (5’UTR) of transcripts, which can regulate translation of the correspondent main open reading frame (mORF). During endoplasmic reticulum (ER) stress, the accumulation of unfolded proteins activates the ER-resident PKR-like ER kinase (PERK), which results in phosphorylation of eIF2α to inhibit global mRNA translation, while allowing the selective uORF-mediated translation of downstream effectors responsible for stress resolution or, ultimately, cell death. The dual role of PERK in regulating cell fate was implicated in human diseases, like diabetes, neurodegenerative disorders and cancer. Moreover, mutations in the EIF2AK3 gene (encoding PERK) were associated to the rare genetic disease, Wolcott-Rallison Syndrome (WRS). In this work, we aimed to study the translational regulatory role of 5 AUG- and 3 non-AUG-uORFs identified in the PERK 5’UTR and assess its biological relevance. While uORF2 and the non-AUG-uORFs 5, 6 and 7 (numbered according to their distance to the 5’ end of the mRNA) do not seem to have a regulatory role, uORF1, uORF3, uORF4 and uORF8 together present a strong repressive effect over mORF translation in basal conditions. Also, we observe that uORF1 is frequently translated allowing low levels of translation re-initiation at the main ORF. Curiously, we found that when PERK is overexpressed, it leads to the spontaneous activation of a portion of PERK in the absence of any stress stimulus, possibly highlighting the biological relevance of its uORF-mediated translational regulation. Conversely, during ER stress, increased bypass of uORF1 results in a modest degree of translational de-repression, which may help to counterbalance the increased rate of PERK protein turnover observed in these conditions. We also observed that alteration of the PERK uORFs by mutations found in WRS patients modify mORF expression, providing a possible link to the disease. Altogether, we highlight the importance of including 5’UTRs in the screening of disease-related mutations and the necessity of functional studies to assess their role in pathogenesis.pt_PT
dc.description.sponsorshipPartially supported by UID/MULTI/04046/2013 center grant from FCT to BioISI. RF is recipient of a fellowship from BioSys PhD programme (SFRH/BD/114392/2016) from FCT.pt_PT
dc.description.versionN/Apt_PT
dc.identifier.urihttp://hdl.handle.net/10400.18/8133
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.relationBiosystems & Integrative Sciences Institute
dc.relationThe interplay between nonsense-mediated mRNA decay NMD and the unfolded protein response UPR: implications for physiology and myocardial infarction. - Regulation of nonsesnse.mediated MRNA decay NMD and the transcriptome: implications for physiology and myocrdial infarction
dc.subjectUpstream Open Reading Framespt_PT
dc.subjectPERK Translationpt_PT
dc.subjectDoenças Genéticaspt_PT
dc.subjectGenómica Funcionalpt_PT
dc.subjectGenómica Funcional e Estruturalpt_PT
dc.titleRegulation of the Human PERK mRNA Translation by Upstream Open Reading Framespt_PT
dc.typeconference object
dspace.entity.typePublication
oaire.awardTitleBiosystems & Integrative Sciences Institute
oaire.awardTitleThe interplay between nonsense-mediated mRNA decay NMD and the unfolded protein response UPR: implications for physiology and myocardial infarction. - Regulation of nonsesnse.mediated MRNA decay NMD and the transcriptome: implications for physiology and myocrdial infarction
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FMulti%2F04046%2F2013/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/PD%2FBD%2F114392%2F2016/PT
oaire.citation.conferencePlace(Online)pt_PT
oaire.citation.title26th Annual Meeting of the RNA Society (RNA 2021), 25 May-4 June 2021pt_PT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStreamOE
person.familyNameRomão
person.givenNameLuísa
person.identifierhttps://scholar.google.pt/citations?hl=pt-PT&user=CAHjIsoAAAAJ&cstart=60&pagesize=20
person.identifier.ciencia-idEB19-DF07-EB37
person.identifier.orcid0000-0002-5061-5287
person.identifier.scopus-author-idhttp://www.scopus.com/authid/detail.url?authorId=6602834878
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsembargoedAccesspt_PT
rcaap.typeconferenceObjectpt_PT
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