Abstract
Newly synthesized proteins co-translationally inserted into the endoplasmic reticulum (ER) lumen may be recruited into anterograde transport vesicles by their association with specific cargo receptors. We recently identified a role for the cargo receptor SURF4 in facilitating the secretion of PCSK9 in cultured cells. To examine the function of SURF4 in vivo, we used CRISPR/Cas9-mediated gene editing to generate mice with germline loss-of-function mutations in Surf4. Heterozygous Surf4+/- mice exhibit grossly normal appearance, behavior, body weight, fecundity, and organ development, with no significant alterations in circulating plasma levels of PCSK9, apolipoprotein B, or total cholesterol, and a detectable accumulation of intrahepatic apoliprotein B. Homozygous Surf4-/- mice exhibit embryonic lethality, with complete loss of all Surf4-/- offspring between embryonic days 3.5 and 9.5. In contrast to the milder murine phenotypes associated with deficiency of known SURF4 cargoes, the embryonic lethality of Surf4-/- mice implies the existence of additional SURF4 cargoes or functions that are essential for murine early embryonic development.
Highlights
The coatomer protein complex II (COPII) coat assembles on the cytoplasmic surface of endoplasmic reticulum (ER) exit sites to drive the formation of membrane-bound transport vesicles
Through unbiased genome-scale CRISPR screening, we recently discovered a role for the ER cargo receptor Surfeit locus protein 4 (SURF4) in the secretion of Proprotein convertase subtilisin/kexin type 9 (PCSK9)[3], a protein that modulates mammalian cholesterol homeostasis through its negative regulation of the Low-density lipoprotein receptor (LDLR)[4]
We found that partial loss of SURF4 in heterozygous mice led to a modest accumulation of intrahepatic apolipoprotein B, with no effect on steady state plasma levels
Summary
The coatomer protein complex II (COPII) coat assembles on the cytoplasmic surface of endoplasmic reticulum (ER) exit sites to drive the formation of membrane-bound transport vesicles. Efficient recruitment of proteins and lipids into these vesicles occurs via physical interaction with the COPII coat[1]. For cargoes accessible on the cytoplasmic surface of the ER membrane, this interaction may be direct. For soluble cargoes in the ER lumen, transmembrane cargo receptors serve as intermediaries for this interaction[2]. Thousands of human proteins traffic through the secretory pathway, a corresponding cargo receptor.
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