Title : Endopeptidase cleavage generates a functionally distinct
isoform of
C1q /tumor necrosis factor-related
protein-12 (
CTRP12 ) with an altered oligomeric state and signaling specificity
Abstract :
- 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 pro protein 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 f CTRP12 strongly activated Akt signaling in H4IIE hepatocytes and 3T3-L1 adipocytes, gCTRP12 preferentially activated MAP kinase ( ERK1/2 and p38 MAPK) signaling
- Further, only f CTRP12 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
Output (sent_index, trigger,
protein,
sugar,
site):
- 5. glycosylated, , -, -, Asn(39)
Output(Part-Of) (sent_index,
protein,
site):
*Output_Site_Fusion* (sent_index,
protein,
sugar,
site):