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면역미생물공생연구단
면역 미생물 공생 연구단
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KLK5 induces shedding of DPP4 from circulatory Th17 cells in type 2 diabetes

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Title
KLK5 induces shedding of DPP4 from circulatory Th17 cells in type 2 diabetes
Author(s)
Titli Nargis; Krishna Kumar; Amrit Raj Ghosh; Amit Sharma; Dipayan Rudra; Debrup Sen; Saikat Chakrabarti; Satinath Mukhopadhyay; Dipyaman Ganguly; Partha Chakrabarti
Publication Date
2017-11
Journal
Molecular Metabolism, v.6, no.11, pp.1529 - 1539
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. © 2017 The Author. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
URI
http://pr.ibs.re.kr/handle/8788114/4190
DOI
10.1016/j.molmet.2017.09.004
ISSN
2212-8778
Appears in Collections:
Academy of Immunology and Microbiology(면역 미생물 공생 연구단) > Journal Papers (저널논문)
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