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Functional overlap between the mammalian Sar1a and Sar1b paralogs in vivo.
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.
Afiliação
  • Tang VT; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109.
  • Xiang J; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109.
  • Chen Z; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109.
  • McCormick J; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109.
  • Abbineni PS; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109.
  • Chen XW; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109.
  • Hoenerhoff M; Department of Microbiology and Immunology, Loyola University Chicago Stritch School of Medicine, Maywood, IL 60153.
  • Emmer BT; State Key Laboratory of Membrane Biology, Peking University, Beijing 100871, China.
  • Khoriaty R; Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI 48109.
  • Lin JD; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109.
  • Ginsburg D; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109.
Proc Natl Acad Sci U S A ; 121(19): e2322164121, 2024 May 07.
Article em En | MEDLINE | ID: mdl-38687799
ABSTRACT
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 ~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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Monoméricas de Ligação ao GTP Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Monoméricas de Ligação ao GTP Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article