Functional overlap between the mammalian Sar1a and Sar1b paralogs in vivo

• 成果类型: Article
• 署名作者: Tang, Vi T.; Xiang, Jie; Chen, Zhimin; McCormick, Joseph; Abbineni, Prabhodh S.; Chen, Xiao-Wei; Hoenerhoff, Mark; Emmer, Brian T.; Khoriaty, Rami; Lin, Jiandie D.; Ginsburg, David
• 署名单位: University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; Loyola University Chicago; Peking University; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14436
• DOI: 10.1073/pnas.2322164121
• 发表日期: 2024-05-07
• 关键词: genome-wide; copii; mutations; gtpase; resource; sec23b; mice

摘要

Proteins 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 two SAR1 paralogs, SAR1A and SAR1B. While these paralogs exhibit similar to 90% amino acid sequence identity, it is unknown whether they perform distinct or overlapping functions in vivo. We now report that genetic inactivation of Sar1a in mice results in lethality during midembryogenesis. We also confirm previous reports that complete deficiency of murine Sar1b results in perinatal lethality. In contrast, we demonstrate that deletion of Sar1b restricted 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 two paralogs, we genetically engineered mice with the Sar1a coding sequence replacing that of Sar1b at the endogenous Sar1b locus. 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 of SAR1A gene expression as a potential approach for the treatment of SAR1B deficiency (chylomicron retention disease) in humans.