KLK5 induces shedding of DPP4 from circulatory Th17 cells in type 2 diabetes.
Mol Metab
; 6(11): 1529-1539, 2017 11.
Article
in En
| MEDLINE
| ID: mdl-29107298
ABSTRACT
OBJECTIVE:
Increasing plasma levels and activity of dipeptidyl peptidase-4 (DPP4 or CD26) are associated with rapid progression of metabolic syndrome to overt type 2 diabetes mellitus (T2DM). While DPP4 inhibitors are increasingly used as anti-hyperglycemic agents, the reason for the increase in plasma DPP4 activity in T2DM patients remains elusive.METHODS:
We looked into the source of plasma DPP4 activity in a cohort of 135 treatment naive nonobese (BMI < 30) T2DM patients. A wide array of ex vivo, in vitro, and in silico methods were employed to study enzyme activity, gene expression, subcellular localization, protease identification, surface expression, and protein-protein interactions.RESULTS:
We show that circulating immune cells, particularly CD4+ T cells, served as an important source for the increase in plasma DPP4 activity in T2DM. Moreover, we found kallikrein-related peptidase 5 (KLK5) as the enzyme responsible for cleaving DPP4 from the cell surface by directly interacting with the extracellular loop. Expression and secretion of KLK5 is induced in CD4+ T cells of T2DM patients. In addition, KLK5 shed DPP4 from circulating CD4+ T helper (Th)17 cells and shed it into the plasma of T2DM patients. Similar cleavage and shedding activities were not seen in controls.CONCLUSIONS:
Our study provides mechanistic insights into the molecular interaction between KLK5 and DPP4 as well as CD4+ T cell derived KLK5 mediated enzymatic cleavage of DPP4 from cell surface. Thus, our study uncovers a hitherto unknown cellular source and mechanism behind enhanced plasma DPP4 activity in T2DM.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Kallikreins
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Dipeptidyl Peptidase 4
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Diabetes Mellitus, Type 2
/
Th17 Cells
Limits:
Adult
/
Female
/
Humans
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Male
/
Middle aged
Language:
En
Journal:
Mol Metab
Year:
2017
Document type:
Article
Affiliation country: