KLK5 induces shedding of DPP4 from circulatory Th17 cells in type 2 diabetes

Mol Metab. 2017 Nov;6(11):1529-1539. doi: 10.1016/j.molmet.2017.09.004. Epub 2017 Sep 27.

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.

Keywords: DPP4; KLK5; PBMC; T2DM; Th17 cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • CD4-Positive T-Lymphocytes / enzymology
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / enzymology*
  • Diabetes Mellitus, Type 2 / genetics
  • Dipeptidyl Peptidase 4 / blood*
  • Female
  • Humans
  • Kallikreins / blood*
  • Kallikreins / genetics
  • Male
  • Middle Aged
  • Th17 Cells / enzymology*

Substances

  • DPP4 protein, human
  • Dipeptidyl Peptidase 4
  • KLK5 protein, human
  • Kallikreins