Functions of the COPII gene paralogs SEC23A and SEC23B are interchangeable in vivo

Abstract

Approximately one-third of the mammalian proteome is transported from the endoplasmic reticulum-to-Golgi via COPII-coated vesicles. SEC23, a core component of coat protein-complex II (COPII), is encoded by two paralogous genes in vertebrates ( and ). In humans, SEC23B deficiency results in congenital dyserythropoietic anemia type-II (CDAII), while SEC23A deficiency results in a skeletal phenotype (with normal red blood cells). These distinct clinical disorders, together with previous biochemical studies, suggest unique functions for SEC23A and SEC23B. Here we show indistinguishable intracellular protein interactomes for human SEC23A and SEC23B, complementation of yeast Sec23 by both human and murine SEC23A/B, and rescue of the lethality of deficiency in zebrafish by a -expressing transgene. We next demonstrate that a coding sequence inserted into the murine locus completely rescues the lethal SEC23B-deficient pancreatic phenotype. We show that SEC23B is the predominantly expressed paralog in human bone marrow, but not in the mouse, with the reciprocal pattern observed in the pancreas. Taken together, these data demonstrate an equivalent function for SEC23A/B, with evolutionary shifts in the transcription program likely accounting for the distinct phenotypes of SEC23A/B deficiency within and across species, a paradigm potentially applicable to other sets of paralogous genes. These findings also suggest that enhanced erythroid expression of the normal gene could offer an effective therapeutic approach for CDAII patients.

Murine Surf4 is essential for early embryonic development

“…Recent characterizations of mice with genetic deficiency of COPII components have extended these findings to mammalian physiology, revealing a variety of complex phenotypes [8][9][10][11][12][13][14][15][16][17] .…”

Characterization of the interactions between Codanin-1 and C15Orf41, two proteins implicated in congenital dyserythropoietic anemia type I disease

“…As the coat proteins serve essential roles in all tissues and cells, the reason for the erythroid-specific phenotypes is not clear. It has recently been suggested that in human (but not in mouse) SEC23B is highly expressed in the erythroid system and thus uniquely affects this system [3]. The key CDA type III characteristic is giant multinucleate erythroblasts with up to 12 nuclei per cell.…”

Recent gene duplications dominate evolutionary dynamics of adaptor protein complex subunits in embryophytes

“…This result leads to the question of why the paralogues identified in this study were retained. One possibility is that multiple copies of a gene may be retained simply because their promoters lose effectiveness in different cell types or developmental stages . For example, the two paralogues of the Sec23 subunit of COat Protein complex II (COPII) in mammalian cells, which originated from a duplication occurring early in vertebrate evolution, have different tissue‐specific expression patterns, but indistinguishable interactomes .…”

“…One possibility is that multiple copies of a gene may be retained simply because their promoters lose effectiveness in different cell types or developmental stages . For example, the two paralogues of the Sec23 subunit of COat Protein complex II (COPII) in mammalian cells, which originated from a duplication occurring early in vertebrate evolution, have different tissue‐specific expression patterns, but indistinguishable interactomes . A corollary of this is that although there may be multiple paralogues present for a given complex subunit, they may not be expressed simultaneously in the same cells, therefore perhaps contributing little to complexity at the cellular level.…”