The Ashwell receptor mitigates the lethal coagulopathy of sepsis.
The Ashwell receptor, the major lectin of hepatocytes, rapidly clears from blood circulation glycoproteins bearing glycan ligands that include galactose and N-acetylgalactosamine. This asialoglycoprotein receptor activity remains a key factor in the development and administration of glycoprotein pharmaceuticals, yet a biological purpose of the Ashwell receptor has remained elusive. We have identified endogenous ligands of the Ashwell receptor as glycoproteins and regulatory components in blood coagulation and thrombosis that include von Willebrand factor (vWF) and platelets. The Ashwell receptor normally modulates vWF homeostasis and is responsible for thrombocytopenia during systemic Streptococcus pneumoniae infection by eliminating platelets desialylated by the bacterium's neuraminidase. Hemostatic adaptation by the Ashwell receptor moderates the onset and severity of disseminated intravascular coagulation during sepsis and improves the probability of host survival.
Grewal
Prabhjit K
PK
The Howard Hughes Medical Institute and Department of Cellular and Molecular Medicine University of California, San Diego, La Jolla, California 92093, USA.
Uchiyama
Satoshi
S
Ditto
David
D
Varki
Nissi
N
Le
Dzung T
DT
Nizet
Victor
V
Marth
Jamey D
JD
D000818:Animals; D037263:Asialoglycoprotein Receptor / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D001212:Asialoglycoproteins / Q000097:blood / Q000493:pharmacokinetics; D001778:Blood Coagulation Disorders / Q000097:blood* / Q000473:pathology*; D001792:Blood Platelets / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D004195:Disease Models, Animal; D019084:Fluorescent Antibody Technique, Indirect; D006487:Hemostasis / Q000502:physiology; D022781:Hepatocytes / Q000737:chemistry / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D008024:Ligands; D008657:Metabolic Clearance Rate / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D011008:Pneumococcal Infections / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D013921:Thrombocytopenia / Q000382:microbiology / Q000473:pathology; D014841:von Willebrand Factor / Q000378:metabolism
D037263:Asialoglycoprotein Receptor; D001212:Asialoglycoproteins; D008024:Ligands; D014841:von Willebrand Factor