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Article: N-linked glycosylation is required for optimal proteolytic activation of membrane-bound transcription factor CREB-H
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TitleN-linked glycosylation is required for optimal proteolytic activation of membrane-bound transcription factor CREB-H
 
AuthorsChan, CP2
Mak, TY2
Chin, KT2 1
Ng, IOL2
Jin, DY2
 
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.
 
CitationJournal Of Cell Science, 2010, v. 123 n. 9, p. 1438-1448 [How to Cite?]
DOI: http://dx.doi.org/10.1242/jcs.067819
 
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.
 
ISSN0021-9533
2013 Impact Factor: 5.325
 
DOIhttp://dx.doi.org/10.1242/jcs.067819
 
ISI Accession Number IDWOS:000276912300008
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.

 
ReferencesReferences in Scopus
 
GrantsCharacterization of fusion oncoprotein FUS-CREB3L2 found in soft tissue sarcoma
Molecular pathology of liver cancer - a multidisciplinary study
 
DC FieldValue
dc.contributor.authorChan, CP
 
dc.contributor.authorMak, TY
 
dc.contributor.authorChin, KT
 
dc.contributor.authorNg, IOL
 
dc.contributor.authorJin, DY
 
dc.date.accessioned2010-12-23T08:32:25Z
 
dc.date.available2010-12-23T08:32:25Z
 
dc.date.issued2010
 
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.
 
dc.description.naturelink_to_OA_fulltext
 
dc.identifier.citationJournal Of Cell Science, 2010, v. 123 n. 9, p. 1438-1448 [How to Cite?]
DOI: http://dx.doi.org/10.1242/jcs.067819
 
dc.identifier.doihttp://dx.doi.org/10.1242/jcs.067819
 
dc.identifier.eissn1477-9137
 
dc.identifier.epage1448
 
dc.identifier.hkuros176656
 
dc.identifier.hkuros193221
 
dc.identifier.isiWOS:000276912300008
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.

 
dc.identifier.issn0021-9533
2013 Impact Factor: 5.325
 
dc.identifier.issue9
 
dc.identifier.openurl
 
dc.identifier.pmid20356926
 
dc.identifier.scopuseid_2-s2.0-77951722696
 
dc.identifier.spage1438
 
dc.identifier.urihttp://hdl.handle.net/10722/129093
 
dc.identifier.volume123
 
dc.languageeng
 
dc.publisherThe Company of Biologists Ltd.
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofJournal of Cell Science
 
dc.relation.projectCharacterization of fusion oncoprotein FUS-CREB3L2 found in soft tissue sarcoma
 
dc.relation.projectMolecular pathology of liver cancer - a multidisciplinary study
 
dc.relation.referencesReferences in Scopus
 
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.subjectbZIP transcription factors
 
dc.subjectCREB-H
 
dc.subjectEndoplasmic reticulum
 
dc.subjectLiver-enriched transcription factors
 
dc.subjectMembrane-bound transcription factors
 
dc.subjectN-linked glycosylation
 
dc.subjectRegulated intramembrane proteolysis
 
dc.subjectUnfolded protein response
 
dc.titleN-linked glycosylation is required for optimal proteolytic activation of membrane-bound transcription factor CREB-H
 
dc.typeArticle
 
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Author Affiliations
  1. New York University School of Medicine
  2. The University of Hong Kong