title: Peroxisomal localization and circadian regulation of ubiquitin-specific protease 2.
abstract: Temporal regulation of nutrient and energy metabolism is emerging as an important aspect of metabolic homeostasis. The regulatory network that integrates the timing cues and nutritional signals to drive diurnal metabolic rhythms remains poorly defined. The 45-kDa isoform of ubiquitin-specific protease 2 (USP2-45) is a deubiquitinase that regulates hepatic gluconeogenesis and glucose metabolism. In this study, we found that USP2-45 is localized to peroxisomes in hepatocytes through a canonical peroxisome-targeting motif at its C-terminus. Clustering analysis indicates that the expression of a subset of peroxisomal genes exhibits robust diurnal rhythm in the liver. Despite this, nuclear hormone receptor PPARα, a known regulator of peroxisome gene expression, does not induce USP2-45 in hepatocytes and is dispensible for its expression during starvation. In contrast, a functional liver clock is required for the proper nutritional and circadian regulation of USP2-45 expression. At the molecular level, transcriptional coactivators PGC-1α and PGC-1β and repressor E4BP4 exert opposing effects on USP2-45 promoter activity. These studies provide insights into the subcellular localization and transcriptional regulation of a clock-controlled deubiquitinase that regulates glucose metabolism.
authors.affiliation: Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Molusky
authors.forename: Di
authors.initials: D
authors.lastname: Ma
authors.forename: Katie
authors.initials: K
authors.lastname: Buelow
authors.forename: Lei
authors.initials: L
authors.lastname: Yin
authors.forename: Jiandie D
authors.initials: JD
authors.lastname: Lin
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000096:biosynthesis; D002940:Circadian Rhythm; D010450:Endopeptidases / Q000378:metabolism*; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D008969:Molecular Sequence Data; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020675:Peroxisomes / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D015534:Trans-Activators / Q000096:biosynthesis; D014157:Transcription Factors; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; C497441:Nfil3 protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D020033:Protein Isoforms; D015534:Trans-Activators; D014157:Transcription Factors; D010450:Endopeptidases; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases; C579224:Usp2 protein, mouse; D005947:Glucose