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Article: N-linked glycosylation is required for optimal proteolytic activation of membrane-bound transcription factor CREB-H

TitleN-linked glycosylation is required for optimal proteolytic activation of membrane-bound transcription factor CREB-H
Authors
KeywordsbZIP transcription factors
CREB-H
Endoplasmic reticulum
Liver-enriched transcription factors
Membrane-bound transcription factors
N-linked glycosylation
Regulated intramembrane proteolysis
Unfolded protein response
Issue Date2010
PublisherThe Company of Biologists Ltd.
Citation
Journal Of Cell Science, 2010, v. 123 n. 9, p. 1438-1448 How to Cite?
AbstractCREB-H is a liver-enriched bZIP transcription factor of the CREB3 subfamily. CREB-H is activated by intramembrane proteolysis that removes a C-terminal transmembrane domain. Aberrant expression of CREB-H is implicated in liver cancer. In this study we characterized N-linked glycosylation of CREB-H in the luminal domain at the C-terminus. We found that CREB-H is modified at three N-linked glycosylation sites in this region. Disruption of all three sites by site-directed mutagenesis completely abrogated N-linked glycosylation of CREB-H. The unglycosylated mutant of CREB-H was not unstable, unfolded or aggregated. Upon stimulation with an activator of intramembrane proteolysis such as brefeldin A and KDEL-tailed site 1 protease, unglycosylated or deglycosylated CREB-H was largely uncleaved, retained in an inactive form in the endoplasmic reticulum, and less capable of activating transcription driven by unfolded protein response element or C-reactive protein promoter. Taken together, our findings suggest that N-linked glycosylation is required for full activation of CREB-H through intramembrane proteolysis. Our work also reveals a novel mechanism for the regulation of CREB-H-dependent transcription.
Persistent Identifierhttp://hdl.handle.net/10722/129093
ISSN
2014 Impact Factor: 5.432
ISI Accession Number ID
Funding AgencyGrant Number
Hong Kong Research Grants CouncilHKU 7486/06M
HKU 1/06C
Funding Information:

We thank Ron Prywes for the pcDNA3-ATF6 plasmid, and Wilson Ching, Abel Chun, Raven Kok, James Ng, Kam-Leung Siu, Ken Siu, Vincent Tang and Chi-Ming Wong for critical reading of the manuscript. The study was supported by grants HKU 7486/06M and HKU 1/06C from the Hong Kong Research Grants Council.

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorChan, CPen_HK
dc.contributor.authorMak, TYen_HK
dc.contributor.authorChin, KTen_HK
dc.contributor.authorNg, IOLen_HK
dc.contributor.authorJin, DYen_HK
dc.date.accessioned2010-12-23T08:32:25Z-
dc.date.available2010-12-23T08:32:25Z-
dc.date.issued2010en_HK
dc.identifier.citationJournal Of Cell Science, 2010, v. 123 n. 9, p. 1438-1448en_HK
dc.identifier.issn0021-9533en_HK
dc.identifier.urihttp://hdl.handle.net/10722/129093-
dc.description.abstractCREB-H is a liver-enriched bZIP transcription factor of the CREB3 subfamily. CREB-H is activated by intramembrane proteolysis that removes a C-terminal transmembrane domain. Aberrant expression of CREB-H is implicated in liver cancer. In this study we characterized N-linked glycosylation of CREB-H in the luminal domain at the C-terminus. We found that CREB-H is modified at three N-linked glycosylation sites in this region. Disruption of all three sites by site-directed mutagenesis completely abrogated N-linked glycosylation of CREB-H. The unglycosylated mutant of CREB-H was not unstable, unfolded or aggregated. Upon stimulation with an activator of intramembrane proteolysis such as brefeldin A and KDEL-tailed site 1 protease, unglycosylated or deglycosylated CREB-H was largely uncleaved, retained in an inactive form in the endoplasmic reticulum, and less capable of activating transcription driven by unfolded protein response element or C-reactive protein promoter. Taken together, our findings suggest that N-linked glycosylation is required for full activation of CREB-H through intramembrane proteolysis. Our work also reveals a novel mechanism for the regulation of CREB-H-dependent transcription.en_HK
dc.languageengen_US
dc.publisherThe Company of Biologists Ltd.en_US
dc.relation.ispartofJournal of Cell Scienceen_HK
dc.subjectbZIP transcription factorsen_HK
dc.subjectCREB-Hen_HK
dc.subjectEndoplasmic reticulumen_HK
dc.subjectLiver-enriched transcription factorsen_HK
dc.subjectMembrane-bound transcription factorsen_HK
dc.subjectN-linked glycosylationen_HK
dc.subjectRegulated intramembrane proteolysisen_HK
dc.subjectUnfolded protein responseen_HK
dc.subject.meshCell Membrane - drug effects - metabolism-
dc.subject.meshCyclic AMP Response Element-Binding Protein - chemistry - genetics - metabolism-
dc.subject.meshProtein Processing, Post-Translational - drug effects-
dc.subject.meshTranscription, Genetic - drug effects-
dc.subject.meshTranscriptional Activation - drug effects-
dc.titleN-linked glycosylation is required for optimal proteolytic activation of membrane-bound transcription factor CREB-Hen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0021-9533&volume=123&issue=Pt 9&spage=1438&epage=1448&date=2010&atitle=N-linked+glycosylation+is+required+for+optimal+proteolytic+activation+of+membrane-bound+transcription+factor+CREB-Hen_US
dc.identifier.emailNg, IOL:iolng@hkucc.hku.hken_HK
dc.identifier.emailJin, DY:dyjin@hkucc.hku.hken_HK
dc.identifier.authorityNg, IOL=rp00335en_HK
dc.identifier.authorityJin, DY=rp00452en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1242/jcs.067819en_HK
dc.identifier.pmid20356926en_HK
dc.identifier.scopuseid_2-s2.0-77951722696en_HK
dc.identifier.hkuros176656en_US
dc.identifier.hkuros193221-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77951722696&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume123en_HK
dc.identifier.issue9en_HK
dc.identifier.spage1438en_HK
dc.identifier.epage1448en_HK
dc.identifier.eissn1477-9137-
dc.identifier.isiWOS:000276912300008-
dc.publisher.placeUnited Kingdomen_HK
dc.relation.projectCharacterization of fusion oncoprotein FUS-CREB3L2 found in soft tissue sarcoma-
dc.relation.projectMolecular pathology of liver cancer - a multidisciplinary study-
dc.identifier.scopusauthoridChan, CP=36193690700en_HK
dc.identifier.scopusauthoridMak, TY=36194013400en_HK
dc.identifier.scopusauthoridChin, KT=7202995491en_HK
dc.identifier.scopusauthoridNg, IOL=7102753722en_HK
dc.identifier.scopusauthoridJin, DY=7201973614en_HK

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