title: Regulation of G0/G1 Switch Gene 2 (G0S2) Protein Ubiquitination and Stability by Triglyceride Accumulation and ATGL Interaction.
abstract: Intracellular triglyceride (TG) hydrolysis or lipolysis is catalyzed by the key intracellular triglyceride hydrolase, adipose triglyceride lipase (ATGL). The G0/G1 Switch Gene 2 (G0S2) was recently identified as the major selective inhibitor of ATGL and its hydrolase function. Since G0S2 levels are dynamically linked and rapidly responsive to nutrient status or metabolic requirements, the identification of its regulation at the protein level is of significant value. Earlier evidence from our laboratory demonstrated that G0S2 is a short-lived protein degraded through the proteasomal pathway. However, little is currently known regarding the underlying mechanisms. In the current study we find that 1) protein degradation is initiated by K48-linked polyubiquitination of the lysine- 25 in G0S2; and 2) G0S2 protein is stabilized in response to ATGL expression and TG accumulation. Mutation of lysine-25 of G0S2 abolished ubiquitination and increased protein stability. More importantly, G0S2 was stabilized via different mechanisms in the presence of ATGL vs. in response to fatty acid (FA)-induced TG accumulation. Furthermore, G0S2 protein but not mRNA levels were reduced in the adipose tissue of ATGL-deficient mice, corroborating the involvement of ATGL in the stabilization of G0S2. Taken together our data illustrate for the first time a crucial multifaceted mechanism for the stabilization of G0S2 at the protein level.
authors.affiliation: Department of Biochemistry & Molecular Biology, Mayo Clinic College of Medicine, Scottsdale, Arizona, United States of America.|Metabolic HEALth Program, Mayo Clinic, Scottsdale, Arizona, United States of America.|Mayo Graduate School, Rochester, Minnesota, United States of America.
authors.forename: Bradlee L
authors.initials: BL
authors.lastname: Heckmann
authors.affiliation: Department of Biochemistry & Molecular Biology, Mayo Clinic College of Medicine, Scottsdale, Arizona, United States of America.|Metabolic HEALth Program, Mayo Clinic, Scottsdale, Arizona, United States of America.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry & Molecular Biology, Mayo Clinic College of Medicine, Scottsdale, Arizona, United States of America.|Metabolic HEALth Program, Mayo Clinic, Scottsdale, Arizona, United States of America.
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Saarinen
authors.affiliation: Department of Biochemistry & Molecular Biology, Mayo Clinic College of Medicine, Scottsdale, Arizona, United States of America.|Metabolic HEALth Program, Mayo Clinic, Scottsdale, Arizona, United States of America.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D016193:G1 Phase; D008049:Lipase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding; D016192:Resting Phase, Cell Cycle; D014280:Triglycerides / Q000378:metabolism*; D054875:Ubiquitination; D000217:Acyltransferases
chemical_list: D018797:Cell Cycle Proteins; D008049:Lipase; D014280:Triglycerides; C508072:G0S2 protein, mouse; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases