Abstract
Misfolding of proteins during endoplasmic reticulum (ER) stress results in the formation of cytotoxic aggregates. The ER-associated degradation pathway counteracts such aggregation through the elimination of misfolded proteins by the ubiquitin-proteasome system. We now show that SHP substrate-1 (SHPS-1), a transmembrane glycoprotein that regulates cytoskeletal reorganization and cell-cell communication, is a physiological substrate for the Skp1-Cullin1-NFB42-Rbx1 (SCF(NFB42)) E3 ubiquitin ligase, a proposed mediator of ER-associated degradation. SCF(NFB42) mediated the polyubiquitination of immature SHPS-1 and its degradation by the proteasome. Ectopic expression of NFB42 both suppressed the formation of aggresome-like structures and the phosphorylation of the translational regulator eIF2alpha induced by overproduction of SHPS-1 as well as increased the amount of mature SHPS-1 at the cell surface. An NFB42 mutant lacking the F box domain had no such effects. Our results suggest that SCF(NFB42) regulates SHPS-1 biosynthesis in response to ER stress.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Antigens, Differentiation / biosynthesis*
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Antigens, Differentiation / genetics
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Antigens, Differentiation / metabolism
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Base Sequence
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Cell Cycle Proteins / metabolism
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Cell Line
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Cysteine Endopeptidases / metabolism
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DNA Primers
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Endoplasmic Reticulum / metabolism*
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Fluorescent Antibody Technique
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Membrane Glycoproteins / biosynthesis*
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism
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Molecular Sequence Data
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Multienzyme Complexes / metabolism
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Mutagenesis, Site-Directed
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Nerve Tissue Proteins / metabolism
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Neural Cell Adhesion Molecule L1 / biosynthesis*
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Neural Cell Adhesion Molecule L1 / genetics
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Neural Cell Adhesion Molecule L1 / metabolism
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Proteasome Endopeptidase Complex
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Receptors, Immunologic / biosynthesis*
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Receptors, Immunologic / genetics
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Receptors, Immunologic / metabolism
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S-Phase Kinase-Associated Proteins / metabolism
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Ubiquitin / metabolism*
Substances
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Antigens, Differentiation
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Cell Cycle Proteins
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DNA Primers
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Membrane Glycoproteins
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Multienzyme Complexes
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Nerve Tissue Proteins
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Neural Cell Adhesion Molecule L1
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Receptors, Immunologic
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S-Phase Kinase-Associated Proteins
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Ubiquitin
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex