Functional overlap between the mammalianSar1aandSar1bparalogs in vivo

Abstract

AbstractProteins carrying a signal peptide and/or a transmembrane domain enter the intracellular secretory pathway at the endoplasmic reticulum (ER) and are transported to the Golgi apparatus via COPII vesicles or tubules. SAR1 initiates COPII coat assembly by recruiting other coat proteins to the ER membrane. Mammalian genomes encode twoSAR1paralogs,SAR1AandSAR1B. While these paralogs exhibit ∼90% amino acid sequence identity, it is unknown whether they perform distinct or overlapping functions in vivo. We now report that genetic inactivation ofSar1ain mice results in lethality during mid-embryogenesis. We also confirm previous reports that complete deficiency of murineSar1bresults in perinatal lethality. In contrast, we demonstrate that deletion ofSar1brestricted to hepatocytes is compatible with survival, though resulting in hypocholesterolemia that can be rescued by adenovirus-mediated overexpression of either SAR1A or SAR1B. To further examine the in vivo function of these 2 paralogs, we genetically engineered mice with theSar1acoding sequence replacing that ofSar1bat the endogenousSar1blocus. Mice homozygous for this allele survive to adulthood and are phenotypically normal, demonstrating complete or near-complete overlap in function between the two SAR1 protein paralogs in mice. These data also suggest upregulation ofSAR1Agene expression as a potential approach for the treatment of SAR1B deficiency (chylomicron retention disease) in humans.