Sex-Specific Linear Polyubiquitination Is a Critical Regulator of Contextual Fear Memory Formation

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dc.contributor.authorMusaus, Madelineen
dc.contributor.authorFarrell, Kaylaen
dc.contributor.authorNavabpour, Shaghayeghen
dc.contributor.authorRay, W. Keithen
dc.contributor.authorHelm, Richard F.en
dc.contributor.authorJarome, Timothy J.en
dc.date.accessioned2022-01-19T20:41:01Zen
dc.date.available2022-01-19T20:41:01Zen
dc.date.issued2021-07-09en
dc.date.updated2022-01-19T20:40:57Zen
dc.description.abstractStrong evidence supports that protein ubiquitination is a critical regulator of fear memory formation. However, as this work has focused on protein degradation, it is currently unknown whether polyubiquitin modifications that are independent of the proteasome are involved in learning-dependent synaptic plasticity. Here, we present the first evidence that atypical linear (M1) polyubiquitination, the only ubiquitin chain that does not occur at a lysine site and is largely independent of the proteasome, is critically involved in contextual fear memory formation in the amygdala in a sex-specific manner. Using immunoblot and unbiased proteomic analyses, we found that male (49) and female (14) rats both had increased levels of linear polyubiquitinated substrates following fear conditioning, though none of these protein targets overlapped between sexes. In males, target protein functions involved cell junction and axonal guidance signaling, while in females the primary target was Adiponectin A, a critical regulator of neuroinflammation, synaptic plasticity, and memory, suggesting sex-dependent functional roles for linear polyubiquitination during fear memory formation. Consistent with these increases, in vivo siRNA-mediated knockdown of Rnf31, an essential component of the linear polyubiquitin E3 complex LUBAC, in the amygdala impaired contextual fear memory in both sexes without affecting memory retrieval. Collectively, these results provide the first evidence that proteasome-independent linear polyubiquitination is a critical regulator of fear memory formation, expanding the potential roles of ubiquitin-signaling in learning-dependent synaptic plasticity. Importantly, our data identify a novel sex difference in the functional role of, but not a requirement for, linear polyubiquitination in fear memory formation.en
dc.description.versionPublished versionen
dc.format.extent15 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifierARTN 709392 (Article number)en
dc.identifier.doihttps://doi.org/10.3389/fnbeh.2021.709392en
dc.identifier.eissn1662-5153en
dc.identifier.issn1662-5153en
dc.identifier.orcidJarome, Timothy [0000-0001-9189-8992]en
dc.identifier.orcidRay, William [0000-0002-1727-4994]en
dc.identifier.orcidHelm, Richard [0000-0001-5317-0925]en
dc.identifier.pmid34305548en
dc.identifier.urihttp://hdl.handle.net/10919/107792en
dc.identifier.volume15en
dc.language.isoenen
dc.publisherFrontiersen
dc.relation.urihttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000675624200001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=930d57c9ac61a043676db62af60056c1en
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectLife Sciences & Biomedicineen
dc.subjectBehavioral Sciencesen
dc.subjectNeurosciencesen
dc.subjectNeurosciences & Neurologyen
dc.subjectubiquitinen
dc.subjectMemoryen
dc.subjectamygdalaen
dc.subjectRNF31en
dc.subjectsiRNAen
dc.subjectUbiquitin-Proteasome Systemen
dc.subjectDependent Protein-Degradationen
dc.subjectSynaptic Plasticityen
dc.subjectUbiquitylated Proteinsen
dc.subjectGustatory Cortexen
dc.subjectChainsen
dc.subjectComplexen
dc.subjectFOXP3en
dc.subjectRNF31en
dc.subjectamygdalaen
dc.subject1109 Neurosciencesen
dc.subject1701 Psychologyen
dc.subject1702 Cognitive Sciencesen
dc.titleSex-Specific Linear Polyubiquitination Is a Critical Regulator of Contextual Fear Memory Formationen
dc.title.serialFrontiers in Behavioral Neuroscienceen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
dcterms.dateAccepted2021-06-22en
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciencesen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciences/Animal and Poultry Sciencesen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciences/Biochemistryen
pubs.organisational-group/Virginia Tech/University Research Institutesen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Life Sciencesen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciences/CALS T&R Facultyen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Life Sciences/Durelle Scotten

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