Glycan-Dependent and -Independent Dual Recognition between DC-SIGN and Type II Serine Protease MSPL/TMPRSS13 in Colorectal Cancer Cells

Motohiro Nonaka,Hiroshi Kido,Nana Kawasaki,Toshisuke Kawasaki,Nobuko Kawasaki,Bruce Yong Ma,Shogo Matsumoto

doi:10.3390/app10082687

Abstract

A class of glycoproteins such as carcinoembryonic antigen (CEA)/CEA-related cell adhesion molecule 1(CEACAM1), CD26 (DPPIV), and mac-2 binding protein (Mac-2BP) harbor tumor-associated glycans in colorectal cancer. In this study, we identified type II transmembrane mosaic serine protease large-form (MSPL) and its splice variant transmembrane protease serine 13 (TMPRSS13) as ligands of Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) on the colorectal cancer cells. DC-SIGN is a C-type lectin expressed on dendritic cells, serves as a pattern recognition receptor for numerous pathogens such as human immunodeficiency virus (HIV) and M. tuberculosis. DC-SIGN recognizes these glycoproteins in a Ca2+ dependent manner. Meanwhile, we found that MSPL proteolytically cleaves DC-SIGN in addition to the above glycan-mediated recognition. DC-SIGN was degraded more efficiently by MSPL when treated with ethylenediaminetetraacetic acid (EDTA), suggesting that glycan-dependent interaction of the two molecules partially blocked DC-SIGN degradation. Our findings uncovered a dual recognition system between DC-SIGN and MSPL/TMPRSS13, providing new insight into the mechanism underlying colorectal tumor microenvironment.

Highlights

Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), a tetrameric transmembrane C-type lectin, which requires calcium for glycan recognition, is expressed in various types of human dendritic cells (DCs), including lymphoid DCs, peripheral blood monocyte-derived DCs (MoDCs), dermal DCs, and DCs in the mucosal epithelium [1,2,3,4]
We previously identified mac-2 binding protein (Mac-2BP) as a DC-SIGN ligand expressed in COLO205 colon cancer cells based on recombinant DC-SIGN-Fc, a fused protein of the DC-SIGN extracellular domain and human
In the results of DC-SIGN-Fc affinity chromatography of the COLO205 membrane protein fraction, we found a sharp band at 100 kDa located above the Mac-2BP band (90 kDa) (Figure 1a)

Summary

Introduction

Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), a tetrameric transmembrane C-type lectin, which requires calcium for glycan recognition, is expressed in various types of human dendritic cells (DCs), including lymphoid DCs, peripheral blood monocyte-derived DCs (MoDCs), dermal DCs, and DCs in the mucosal epithelium [1,2,3,4]. Sci. 2020, 10, 2687 a wide variety of exogenous pathogens, including human immunodeficiency virus (HIV-1) [5], hepatitis C virus [6], Dengue virus [7], M. tuberculosis [8,9,10], and parasites [11]. DC-SIGN facilitates the CD8+ and CD4+ responses by promoting antigen uptake, processing, and presentation on MHC-I/MHC-II molecules, it helps HIV and M. tuberculosis to subvert DC function and escape from intracellular degradation [8,12]. Studies of CD209 promoter gene polymorphism demonstrated that the -336 G variant allele, which is linked to lower DC-SIGN expression, is associated with decreased risk of Dengue fever [7] and tuberculosis [13]. DC-SIGN reportedly activates the serine/threonine kinase Raf-1 upon ligand stimulation and suppresses Toll-like receptor (TLR)-induced immune responses [14,15]

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