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J Biol Chem
2012 Oct 19;28743:35804-14. doi: 10.1074/jbc.M112.365965.
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Endopeptidase cleavage generates a functionally distinct isoform of C1q/tumor necrosis factor-related protein-12 (CTRP12) with an altered oligomeric state and signaling specificity.
Wei Z
,
Lei X
,
Seldin MM
,
Wong GW
.
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Adipose tissue-derived adipokines are an important class of secreted metabolic regulators that mediate tissue cross-talk to control systemic energy balance. We recently described C1q/TNF-related protein-12 (CTRP12), a novel insulin-sensitizing adipokine that regulates glucose metabolism in liver and adipose tissue. However, the biochemical properties of CTRP12 and its naturally occurring cleaved isoform have not been characterized. Here, we show that CTRP12 is a secreted hormone subjected to multiple functionally relevant posttranslational modifications at highly conserved residues. For example, Asn(39) is glycosylated, whereas Cys(85) mediates the assembly of higher order oligomeric structure. Endopeptidase cleavage at Lys(91) generates a cleaved globular gCTRP12 isoform, the expression of which is increased by insulin. PCSK3/furin was identified as the major proprotein convertase expressed by adipocytes that mediates the endogenous cleavage of CTRP12. Cleavage at Lys(91) is context-dependent: mutation of the charged Arg(93) to Ala on the P2' position enhanced cleavage, and triple mutations (K90A/K91A/R93A) abolished cleavage. Importantly, the two isoforms of CTRP12 differ in oligomeric structures and are functionally distinct. The full-length protein forms trimers and larger complexes, and the cleaved isoform consisted of predominantly dimers. Whereas full-length fCTRP12 strongly activated Akt signaling in H4IIE hepatocytes and 3T3-L1 adipocytes, gCTRP12 preferentially activated MAP kinase (ERK1/2 and p38 MAPK) signaling. Further, only fCTRP12 improved insulin-stimulated glucose uptake in adipocytes. These results reveal a novel mechanism controlling signaling specificity and function of a hormone via cleavage-dependent alteration in oligomeric state.
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Ayyagari,
Late-onset macular degeneration and long anterior lens zonules result from a CTRP5 gene mutation.
2005,
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Basak,
In vitro elucidation of substrate specificity and bioassay of proprotein convertase 4 using intramolecularly quenched fluorogenic peptides.
2004,
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Briggs,
Role of redox environment on the oligomerization of higher molecular weight adiponectin.
2011,
Pubmed
Chavali,
A CTRP5 gene S163R mutation knock-in mouse model for late-onset retinal degeneration.
2011,
Pubmed
Deng,
Adipokines as novel biomarkers and regulators of the metabolic syndrome.
2010,
Pubmed
Enomoto,
Adipolin/C1qdc2/CTRP12 protein functions as an adipokine that improves glucose metabolism.
2011,
Pubmed
Hayward,
Mutation in a short-chain collagen gene, CTRP5, results in extracellular deposit formation in late-onset retinal degeneration: a genetic model for age-related macular degeneration.
2003,
Pubmed
Jaeken,
Congenital disorders of glycosylation: a rapidly expanding disease family.
2007,
Pubmed
Kishore,
C1q and tumor necrosis factor superfamily: modularity and versatility.
2004,
Pubmed
Kopp,
Effects of the new adiponectin paralogous protein CTRP-3 and of LPS on cytokine release from monocytes of patients with type 2 diabetes mellitus.
2010,
Pubmed
Kopp,
C1q/TNF-related protein-3 represents a novel and endogenous lipopolysaccharide antagonist of the adipose tissue.
2010,
Pubmed
Lasser,
C1qTNF-related protein-1 (CTRP-1): a vascular wall protein that inhibits collagen-induced platelet aggregation by blocking VWF binding to collagen.
2006,
Pubmed
Maeda,
Molecular cloning and characterization of a novel gene, CORS26, encoding a putative secretory protein and its possible involvement in skeletal development.
2001,
Pubmed
Maeda,
Cartducin, a paralog of Acrp30/adiponectin, is induced during chondrogenic differentiation and promotes proliferation of chondrogenic precursors and chondrocytes.
2006,
Pubmed
Peterson,
CTRP1 protein enhances fatty acid oxidation via AMP-activated protein kinase (AMPK) activation and acetyl-CoA carboxylase (ACC) inhibition.
2012,
Pubmed
Peterson,
C1q/TNF-related protein-3 (CTRP3), a novel adipokine that regulates hepatic glucose output.
2010,
Pubmed
Scherer,
Adipose tissue: from lipid storage compartment to endocrine organ.
2006,
Pubmed
Seidah,
The proprotein convertases, 20 years later.
2011,
Pubmed
Seldin,
Myonectin (CTRP15), a novel myokine that links skeletal muscle to systemic lipid homeostasis.
2012,
Pubmed
Tsao,
Role of disulfide bonds in Acrp30/adiponectin structure and signaling specificity. Different oligomers activate different signal transduction pathways.
2003,
Pubmed
Tsao,
Oligomerization state-dependent activation of NF-kappa B signaling pathway by adipocyte complement-related protein of 30 kDa (Acrp30).
2002,
Pubmed
Wei,
C1q/TNF-related protein-12 (CTRP12), a novel adipokine that improves insulin sensitivity and glycemic control in mouse models of obesity and diabetes.
2012,
Pubmed
Wei,
Metabolic regulation by C1q/TNF-related protein-13 (CTRP13): activation OF AMP-activated protein kinase and suppression of fatty acid-induced JNK signaling.
2011,
Pubmed
Wong,
A family of Acrp30/adiponectin structural and functional paralogs.
2004,
Pubmed
Wong,
Molecular, biochemical and functional characterizations of C1q/TNF family members: adipose-tissue-selective expression patterns, regulation by PPAR-gamma agonist, cysteine-mediated oligomerizations, combinatorial associations and metabolic functions.
2008,
Pubmed
Wong,
Identification and characterization of CTRP9, a novel secreted glycoprotein, from adipose tissue that reduces serum glucose in mice and forms heterotrimers with adiponectin.
2009,
Pubmed
Yan,
Unraveling the mechanism of protein N-glycosylation.
2005,
Pubmed
Zheng,
C1q/TNF-related proteins, a family of novel adipokines, induce vascular relaxation through the adiponectin receptor-1/AMPK/eNOS/nitric oxide signaling pathway.
2011,
Pubmed
