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Competitive oxidation and ubiquitylation on the evolutionarily conserved cysteine confer tissue-specific stabilization of Insig-2
- Source :
- Nature Communications, Nature Communications, Vol 11, Iss 1, Pp 1-13 (2020)
- Publication Year :
- 2020
- Publisher :
- Nature Publishing Group UK, 2020.
-
Abstract
- Insig-2 is an ER membrane protein negatively controlling lipid biosynthesis. Here, we find that Insig-2 is increased in the tissues, including liver, but unaltered in the muscle of gp78-deficient mice. In hepatocytes and undifferentiated C2C12 myoblasts, Insig-2 is ubiquitylated on Cys215 by gp78 and degraded. However, the C215 residue is oxidized by elevated reactive oxygen species (ROS) during C2C12 myoblasts differentiating into myotubes, preventing Insig-2 from ubiquitylation and degradation. The stabilized Insig-2 downregulates lipogenesis through inhibiting the SREBP pathway, helping to channel the carbon flux to ATP generation and protecting myotubes from lipid over-accumulation. Evolutionary analysis shows that the YECK (in which C represents Cys215 in human Insig-2) tetrapeptide sequence in Insig-2 is highly conserved in amniotes but not in aquatic amphibians and fishes, suggesting it may have been shaped by differential selection. Together, this study suggests that competitive oxidation-ubiquitylation on Cys215 of Insig-2 senses ROS and prevents muscle cells from lipid accumulation.<br />The protein Insig-2 negatively regulates lipid biosynthesis and is short-lived in liver cells but stable in muscle cells. Here, the authors show that in muscle cells producing reactive oxygen species, there is increased oxidation compared to ubiquitination of Insig-2, stabilising Insig-2 and reducing lipid biosynthesis.
- Subjects :
- 0301 basic medicine
Male
Muscle Fibers, Skeletal
General Physics and Astronomy
Biochemistry
Myoblasts
Mice
Ubiquitin
Sequence Analysis, Protein
Myocyte
lcsh:Science
Mice, Knockout
Sterol Regulatory Element Binding Proteins
Multidisciplinary
biology
Myogenesis
Chemistry
Fishes
Cell biology
Liver
Lipogenesis
C2C12
Oxidation-Reduction
Evolution
Science
Down-Regulation
CHO Cells
General Biochemistry, Genetics and Molecular Biology
Article
Cell Line
Amphibians
Evolution, Molecular
03 medical and health sciences
Cricetulus
Lipid biosynthesis
Animals
Humans
Cysteine
Muscle Cells
030102 biochemistry & molecular biology
Ubiquitination
Membrane Proteins
Lipid metabolism
General Chemistry
Lipid Metabolism
Sterol regulatory element-binding protein
Mice, Inbred C57BL
Receptors, Autocrine Motility Factor
030104 developmental biology
biology.protein
Hepatocytes
lcsh:Q
Reactive Oxygen Species
Transcriptome
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....3184544df35f8385fe3168769214bfe2