Conference Paper: 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, CP
Mak, TY
Chin, KT
Ng, IOL
Jin, DY
Issue Date2010
CitationHong Kong Inter-University Biochemistry Postgraduate Symposium, CUHK, Hong Kong, 15 May 2010. [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.
DescriptionPlatform Presentations: T01
DC Field
Value
dc.contributor.authorChan, CP
dc.contributor.authorMak, TY
dc.contributor.authorChin, KT
dc.contributor.authorNg, IOL
dc.contributor.authorJin, DY
dc.date.accessioned2010-10-31T12:01:53Z
dc.date.available2010-10-31T12:01:53Z
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.descriptionPlatform Presentations: T01
dc.identifier.citationHong Kong Inter-University Biochemistry Postgraduate Symposium, CUHK, Hong Kong, 15 May 2010. [How to Cite?]
dc.identifier.hkuros182882
dc.identifier.hkuros193224
dc.identifier.openurl
dc.identifier.urihttp://hdl.handle.net/10722/125961
dc.languageeng
dc.relation.ispartofHong Kong Inter-University Biochemistry Postgraduate Symposium
dc.subject.meshAnimals
dc.subject.meshBrefeldin A - pharmacology
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.titleN-linked glycosylation is required for optimal proteolytic activation of membrane-bound transcription factor CREB-H
dc.typeConference_Paper