A new splice variant of the major subunit of human asialoglycoprotein receptor encodes a secreted form in hepatocytes.
BACKGROUND
The human asialoglycoprotein receptor (ASGPR) is composed of two polypeptides, designated H1 and H2. While variants of H2 have been known for decades, the existence of H1 variants has never been reported.


RESULTS
We identified two splice variants of ASGPR H1 transcripts, designated H1a and H1b, in human liver tissues and hepatoma cells. Molecular cloning of ASGPR H1 variants revealed that they differ by a 117 nucleotide segment corresponding to exon 2 in the ASGPR genomic sequence. Thus, ASGPR variant H1b transcript encodes a protein lacking the transmembrane domain. Using an H1b-specific antibody, H1b protein and a functional soluble ASGPR (sASGPR) composed of H1b and H2 in human sera and in hepatoma cell culture supernatant were identified. The expression of ASGPR H1a and H1b in Hela cells demonstrated the different cellular loctions of H1a and H1b proteins at cellular membranes and in intracellular compartments, respectively. In vitro binding assays using fluorescence-labeled sASGPR or the substract ASOR revealed that the presence of sASGPR reduced the binding of ASOR to cells. However, ASOR itself was able to enhance the binding of sASGPR to cells expressing membrane-bound ASGPR. Further, H1b expression is reduced in liver tissues from patients with viral hepatitis.


CONCLUSIONS
We conclude that two naturally occurring ASGPR H1 splice variants are produced in human hepatocytes. A hetero-oligomeric complex sASGPR consists of the secreted form of H1 and H2 and may bind to free substrates in circulation and carry them to liver tissue for uptake by ASGPR-expressing hepatocytes.
Liu
Jia
J
Division of Clinical Immunology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
Hu
Bin
B
Yang
Yan
Y
Ma
Zhiyong
Z
Yu
Yuan
Y
Liu
Shenpei
S
Wang
Baoju
B
Zhao
Xiping
X
Lu
Mengji
M
Yang
Dongliang
D
D037263:Asialoglycoprotein Receptor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D001483:Base Sequence; D002460:Cell Line; D002478:Cells, Cultured; D005110:Extracellular Space / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D012326:RNA Splicing
C546927:ASGR1 protein, human; D037263:Asialoglycoprotein Receptor