Ubiquitination-mediated regulation of biosynthesis of the adhesion receptor SHPS-1 in response to endoplasmic reticulum stress.
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.
Murai-Takebe
Reiko
R
Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Noguchi
Tetsuya
T
Ogura
Takeshi
T
Mikami
Toshiyuki
T
Yanagi
Kazunori
K
Inagaki
Kenjiro
K
Ohnishi
Hiroshi
H
Matozaki
Takashi
T
Kasuga
Masato
M
D000595:Amino Acid Sequence; D000943:Antigens, Differentiation / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism; D017931:DNA Primers; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000378:metabolism; D039842:Neural Cell Adhesion Molecule L1 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011971:Receptors, Immunologic / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*
D000943:Antigens, Differentiation; D018797:Cell Cycle Proteins; D017931:DNA Primers; D008562:Membrane Glycoproteins; D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; D039842:Neural Cell Adhesion Molecule L1; D011971:Receptors, Immunologic; D044786:S-Phase Kinase-Associated Proteins; D025801:Ubiquitin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex