The Function of the COPII Gene Paralogs SEC23A and SEC23B Are Interchangeable In Vivo
Angela C. Weyand,
Mark J. Hoenerhoff,
Elizabeth J. Adams,
Daniel J. Klionsky,
Jordan A. Shavit,
Posted 07 Nov 2017
bioRxiv DOI: 10.1101/215160 (published DOI: 10.1073/pnas.1805784115)
Posted 07 Nov 2017
SEC23 is a core component of the coat protein-complex II (COPII)-coated vesicle, which mediates transport of secretory proteins from the endoplasmic reticulum (ER) to the Golgi. Mammals express 2 paralogs for SEC23 (SEC23A and SEC23B). Though the SEC23 gene duplication dates back >500 million years, both SEC23s are ~85% identical at the amino acid sequence level. In humans, deficiency for SEC23A or SEC23B results in cranio-lenticulo-sutural dysplasia or congenital dyserythropoietic anemia type II (CDAII), respectively. The disparate human syndromes and reports of secretory cargos with apparent paralog-specific dependence, suggest unique functions for the two SEC23 paralogs. Here we show indistinguishable intracellular interactomes for human SEC23A and SEC23B, complementation of yeast SEC23 by both human and murine SEC23A/B paralogs, and the rescue of lethality resulting from Sec23b disruption in zebrafish by a Sec23a-expressing transgene. Finally, we demonstrate that the Sec23a coding sequence inserted into the endogenous murine Sec23b locus fully rescues the mortality and severe pancreatic phenotype previously reported with SEC23B-deficiency in the mouse. Taken together, these data indicate that the disparate phenotypes of SEC23A and SEC23B deficiency likely result from evolutionary shifts in gene expression program rather than differences in protein function, a paradigm likely applicable to other sets of paralogous genes. These findings also suggest the potential for increased expression of SEC23A as a novel therapeutic approach to the treatment of CDAII, with potential relevance to other disorders due to mutations in paralogous genes.
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