Asialoglycoprotein Receptor

Immunoglobulin A (IgA) is the most abundantly produced antibody isotype in mammals. The primary function of IgA is to maintain homeostasis at mucosal surfaces and play a role in immune protection. IgA functions mainly through interaction with multiple receptors, including asialoglycoprotein receptor (ASGPR). ASGPR is a type C, carbohydrate-binding lectin, which mediates clearance of various defective plasma glycoprotein molecules from the body. These receptors also identify and bind to pathogen membrane glycoproteins to efficiently clear them from circulation by receptor-mediated endocytosis and play a pivotal role in preventing hepatocyte infections, inflammation, and cancer. Due to the huge potential of ASGPR in the application of hepatopathies, Creative Biolabs has put effort into the research of ASGPR and gained remarkable achievements. It is a pleasure to share our experience with our partners all over the world and fight against liver diseases together.

Introduction of ASGPR

Cell surface carbohydrate lectins are known to orchestrate a variety of cellular and intercellular functions by specific recognition and binding to various receptors. Of these, the first mammalian cell membrane-bound lectin receptor discovered was ASGPR. ASGP-R has been classically known to recognize desialylated, natural, or synthetic Gal-type ligands including D-galactose (Gal) and D-N-acetyl-galactosamine with a high degree of specificity. ASGP-R is dominant in the liver with an abundant expression on sinusoidal, basolateral membranes of mammalian parenchymal hepatocytes.

Function of ASGPR

The primary physiological function of ASGP-R is specific binding, endocytosis, and clearance of a wide range of circulating desialylated serum glycoproteins by receptor-mediated endocytosis. Altered or reduced expression of this receptor results in elevated plasma levels of these glycoproteins. ASGPR also plays an immunomodulatory role and promotes binding, cellular uptake, and clearance of major plasma proteins. Moreover, the specific localization and high density of ASGPR on the liver cells and subsequent recognition and interactions with cellular components of pathogens play a pivotal role in preventing hepatocyte infections, inflammation, and cancer.

Fig.1 SARS-CoV-2 pseudovirus can infect liver cell lines through ASGR1 in vitro.¹

ASGPR and Diseases

Hepatotropic viruses can enter the hepatocytes through indirect virus/receptor interaction with IgA or fibronectin, which is trapped by ASGPR and triggers complement activation and uptake. While cytokines have been reported to modulate the expression, synthesis, and function of ASGPR, where inflammatory cytokines demonstrated augmented synthesis of the receptor. Therefore, ASGPR is also recognized to act as a self-antigen in the presence of inflammatory diseases, liver injury, or toxins. Therefore, ASGPR has attracted the attention of liver immunologists for many years. This liver-specific lectin was found to be a major B and T cell autoantigenic target in patients with autoimmune liver diseases, and in particular in autoimmune hepatitis.

Fig.2 S SARS-CoV-2 with wild-type Spike infects primary hepatocytes through ASGR1.¹

Moreover, ASGPR expression level in well-differentiated tumors is higher than normal liver tissue and poorly differentiated hepatocellular carcinoma, which suggests that ASGPR can be used in the treatment of early liver cancer, while interaction between IgA and ASGPR provides a novel strategy to design targeted antibody conjugated drugs.

As an important target focus on liver disease, ASGPR attracts more attention from drug development groups including Creative Biolabs. For more details of ASGPR or other research in the field of therapeutic protein research, please feel free to contact us.

Reference

1. Yang, Xinyi, et al. "Asialoglycoprotein receptor 1 promotes SARS-CoV-2 infection of human normal hepatocytes." Signal Transduction and Targeted Therapy 9.1 (2024): 42. Distributed under Open Access license CC BY 4.0, without modification.

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