title: Polyamine regulating protein antizyme binds to ATP citrate lyase to accelerate acetyl-CoA production in cancer cells.
abstract: Antizyme (AZ) regulates cellular polyamines (i.e., putrescine, spermidine, and spermine) through binding to ornithine decarboxylase and subsequent ubiquitin-independent degradation of the enzyme protein by the 26S proteasome. Screening for AZ-binding proteins using a yeast two-hybrid system identified ATP citrate lyase (ACLY), a cytosolic enzyme which catalyzes the production of acetyl-CoA that is used for lipid anabolism or acetylation of cellular components. We confirmed that both AZ1 and AZ2 bind to ACLY and AZ colocalizes with ACLY to the cytoplasm. Unexpectedly, neither AZ1 nor AZ2 accelerated ACLY degradation. Additionally, purified AZ, particularly AZ1, increased the activity of purified ACLY in a dose-dependent manner in vitro, suggesting that AZ activates ACLY through protein-protein interaction. Polyamines themselves had no effect on the ACLY activity in vitro. Knockdown of AZ1 and/or AZ2 in human cancer cells significantly decreased the ACLY activity as well as cellular levels of acetyl-CoA and cholesterol. Our results are the first to show the crosstalk between polyamine and acetyl-CoA metabolism. We hypothesize that AZ may promote acetyl-CoA synthesis to downregulate spermidine and spermine through acetylation.
authors.affiliation: Department of Molecular Biology, The Jikei University School of Medicine, Tokyo 105-8461, Japan.
authors.forename: Ayasa
authors.initials: A
authors.lastname: Tajima
authors.affiliation: Department of Molecular Biology, The Jikei University School of Medicine, Tokyo 105-8461, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Murai
authors.affiliation: Department of Molecular Biology, The Jikei University School of Medicine, Tokyo 105-8461, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Murakami
authors.affiliation: Core Research Facilities for Basic Science (Molecular Cell Biology), The Jikei University School of Medicine, Tokyo 105-8461, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Iwamoto
authors.affiliation: Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Migita
authors.affiliation: Department of Molecular Biology, The Jikei University School of Medicine, Tokyo 105-8461, Japan. Electronic address: senya@jikei.ac.jp.
authors.forename: Senya
authors.initials: S
authors.lastname: Matsufuji
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000378:metabolism*; D000105:Acetyl Coenzyme A / Q000096:biosynthesis*; D000107:Acetylation; D002352:Carrier Proteins; D055785:Gene Knockdown Techniques; D006801:Humans; D050155:Lipogenesis; D009369:Neoplasms / Q000201:enzymology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D013095:Spermidine / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
chemical_list: D002352:Carrier Proteins; D011506:Proteins; C031017:ornithine decarboxylase antizyme; D000105:Acetyl Coenzyme A; D001275:ATP Citrate (pro-S)-Lyase; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D013095:Spermidine
keywords: ATP citrate lyase; Acetyl-CoA; Antizyme; Cholesterol; Polyamine