Details

Autor(en) / Beteiligte

• Nargis, Titli
• Kumar, Krishna
• Ghosh, Amrit Raj
• Sharma, Amit
• Rudra, Dipayan
• Sen, Debrup
• Chakrabarti, Saikat
• Mukhopadhyay, Satinath
• Ganguly, Dipyaman
• Chakrabarti, Partha

Titel

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

Ist Teil von

• Molecular metabolism (Germany), 2017-11, Vol.6 (11), p.1529-1539

Ort / Verlag

Germany: Elsevier GmbH

Erscheinungsjahr

2017

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. 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. 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. 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. [Display omitted] •Plasma DPP4 activity is high in T2DM patients.•PBMC and CD4+ T cells shed increased amount of DPP4 in T2DM patients.•KLK5 expression is enhanced in PBMC and CD4+ T cells in T2DM patients.•CD4+ T cell derived KLK5 induces DPP4 shedding in autocrine and paracrine manner.•Th17 cells are important source of plasma DPP4 in T2DM patients.