TY - JOUR
T1 - The mucinous domain of pancreatic carboxyl-ester lipase (CEL) contains core 1/core 2 O-glycans that can be modified by ABO blood group determinants
AU - Jellas, Khadija El
AU - Johansson, Bente B.
AU - Fjeld, Karianne
AU - Antonopoulos, Aristotelis
AU - Immervoll, Heike
AU - Choi, Man H.
AU - Hoem, Dag
AU - Lowe, Mark E.
AU - Lombardo, Dominique
AU - Njølstad, Pål R.
AU - Dell, Anne
AU - Mas, Eric
AU - Haslam, Stuart M.
AU - Molven, Anders
N1 - Funding Information:
This work was supported by Ph.D. fellowship 911831 (to K. E. J.) and Research Grant 912057 (to A. M.) from Western Norway Regional Health Authority (Helse Vest). The work was also supported by grants from the Gade Legacy (to K. E. J.), Stiftelsen Kristian Gerhard Jebsen (to P. R. N.), Research Council of Norway′s FRIMEDBIO Program (to A. M.), and by Biotechnology and Biological Sciences Research Council Grant BB/K016164/1 (to A. D. and S. M. H.). The authors declare that they have no conflicts of interest with the contents of this article.
Publisher Copyright:
© 2018 El Jellas et al.
PY - 2018/12/14
Y1 - 2018/12/14
N2 - Carboxyl-ester lipase (CEL) is a pancreatic fat-digesting enzyme associated with human disease. Rare mutations in the CEL gene cause a syndrome of pancreatic exocrine and endocrine dysfunction denoted MODY8, whereas a recombined CEL allele increases the risk for chronic pancreatitis. Moreover, CEL has been linked to pancreatic ductal adenocarcinoma (PDAC) through a postulated oncofetal CEL variant termed feto-acinar pancreatic protein (FAPP). The monoclonal antibody mAb16D10 was previously reported to detect a glycotope in the highly O-glycosylated, mucin-like C terminus of CEL/FAPP. We here assessed the expression of human CEL in malignant pancreatic lesions and cell lines. CEL was not detectably expressed in neoplastic cells, implying that FAPP is unlikely to be a glycoisoform of CEL in pancreatic cancer. Testing of the mAb16D10 antibody in glycan microarrays then demonstrated that it recognized structures containing terminal GalNAc-1,3(Fuc-1,2)Gal (blood group A antigen) and also repeated protein sequences containing GalNAc residues linked to Ser/Thr (Tn antigen), findings that were supported by immunostainings of human pancreatic tissue. To examine whether the CEL glycoprotein might be modified by blood group antigens, we used high-sensitivity MALDI-TOF MS to characterize the released O-glycan pool of CEL immunoprecipitated from human pancreatic juice. We found that the O-glycome of CEL consisted mainly of core 1/core 2 structures with a composition depending on the subject’s FUT2 and ABO gene polymorphisms. Thus, among digestive enzymes secreted by the pancreas, CEL is a glycoprotein with some unique characteristics, supporting the view that it could serve additional biological functions to its cholesteryl esterase activity in the duodenum.
AB - Carboxyl-ester lipase (CEL) is a pancreatic fat-digesting enzyme associated with human disease. Rare mutations in the CEL gene cause a syndrome of pancreatic exocrine and endocrine dysfunction denoted MODY8, whereas a recombined CEL allele increases the risk for chronic pancreatitis. Moreover, CEL has been linked to pancreatic ductal adenocarcinoma (PDAC) through a postulated oncofetal CEL variant termed feto-acinar pancreatic protein (FAPP). The monoclonal antibody mAb16D10 was previously reported to detect a glycotope in the highly O-glycosylated, mucin-like C terminus of CEL/FAPP. We here assessed the expression of human CEL in malignant pancreatic lesions and cell lines. CEL was not detectably expressed in neoplastic cells, implying that FAPP is unlikely to be a glycoisoform of CEL in pancreatic cancer. Testing of the mAb16D10 antibody in glycan microarrays then demonstrated that it recognized structures containing terminal GalNAc-1,3(Fuc-1,2)Gal (blood group A antigen) and also repeated protein sequences containing GalNAc residues linked to Ser/Thr (Tn antigen), findings that were supported by immunostainings of human pancreatic tissue. To examine whether the CEL glycoprotein might be modified by blood group antigens, we used high-sensitivity MALDI-TOF MS to characterize the released O-glycan pool of CEL immunoprecipitated from human pancreatic juice. We found that the O-glycome of CEL consisted mainly of core 1/core 2 structures with a composition depending on the subject’s FUT2 and ABO gene polymorphisms. Thus, among digestive enzymes secreted by the pancreas, CEL is a glycoprotein with some unique characteristics, supporting the view that it could serve additional biological functions to its cholesteryl esterase activity in the duodenum.
UR - http://www.scopus.com/inward/record.url?scp=85058547181&partnerID=8YFLogxK
U2 - 10.1074/jbc.RA118.001934
DO - 10.1074/jbc.RA118.001934
M3 - Article
C2 - 30315106
AN - SCOPUS:85058547181
VL - 293
SP - 19476
EP - 19491
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 50
ER -