Abstract
CREB3 is a transcription factor localized to the ER. Here, we investigated endogenous CREB3 expression in HEK293 cells using pharmacological and genome editing approaches. Full-length CREB3 detected under resting conditions disappeared following treatment with tunicamycin, brefeldin A and nigericin. Treatment with cycloheximide and MG132 indicated that endogenous CREB3 is a proteasome substrate. Using cells deficient for the ER-associated protein degradation (ERAD) factors SEL1L and Herp, we demonstrate that SEL1L, but not Herp, plays a crucial role in the posttranslational regulation of full-length CREB3 expression. In addition, kifunensine, an α-mannosidase inhibitor, remarkably increased full-length CREB3 expression. Our study suggests that endogenous full-length CREB3 is a novel substrate for ERAD and identifies unique cellular signals distinct from those in canonical ER stress.
Keywords:
CREB3; ERAD; Herp; SEL1L.
© 2019 Federation of European Biochemical Societies.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Brefeldin A / pharmacology
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Cyclic AMP Response Element-Binding Protein / genetics*
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Cyclic AMP Response Element-Binding Protein / metabolism
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Cycloheximide / pharmacology
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Cysteine Proteinase Inhibitors / pharmacology
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Endoplasmic Reticulum / drug effects
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Endoplasmic Reticulum / metabolism
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HEK293 Cells
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Humans
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Leupeptins / pharmacology
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Nigericin / pharmacology
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Proteasome Endopeptidase Complex / metabolism*
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Protein Synthesis Inhibitors / pharmacology
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Proteins / genetics
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Proteins / metabolism
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Tunicamycin / pharmacology
Substances
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CREB3 protein, human
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Cyclic AMP Response Element-Binding Protein
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Cysteine Proteinase Inhibitors
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HERPUD1 protein, human
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Leupeptins
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Membrane Proteins
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Protein Synthesis Inhibitors
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Proteins
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SEL1L protein, human
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Tunicamycin
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Brefeldin A
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Cycloheximide
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Proteasome Endopeptidase Complex
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde
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Nigericin