Identification of the role of SEL1L in platelet function through a multi-species genetic investigation

SEL1L is a well-known protein in the endoplasmic reticulum associated degradation (ERAD) pathway. While it is known to be expressed in platelets, SEL1L has never been shown to play an active role. Here we find evidence that SEL1L regulates platelet function. We first identified SEL1L through the study of Atypical Equine Thrombasthenia (AET), an autosomal recessive platelet disorder found in Thoroughbred horses. A missense variant in SEL1L (c.1810A>G p.Ile604Val) was found in AET-affected horses, which we show is associated with decreased protein expression. SEL1L is intracellular in equine platelets and localizes to the surface upon activation with thrombin. Platelets from homozygous horses exhibit significant decreases in spreading on immobilized collagen. Human megakaryocytes were found to have two SEL1L protein isoforms that increase in expression during megakaryopoiesis, although only one is delivered to mature platelets. Studies using inducible mouse and constitutive zebrafish knockouts demonstrate that SEL1L is necessary for efficient platelet or thrombocyte (fish equivalent) adhesion to sites of endothelial injury. These data reveal a previously undescribed and conserved role for the ERAD pathway in the etiology of AET and platelet function, which may play a role in human platelet disorders as well. Brief Summary Using a multi-species approach, SEL1L was determined to have a role in platelet function, specifically in helping platelets properly adhere to sites of injury,