Accumulated precursors of specific GPI-anchored proteins upregulate GPI biosynthesis with ARV1

Liu et al. show that precursors of specific GPI-anchored proteins, such as CD55, function with an ER-resident lipid homeostasis regulator ARV1 to upregulate GPI biosynthesis in the ER. This may be an important mechanism to increase GPI when needed. We previously reported that glycosylphosphatidylinositol (GPI) biosynthesis is upregulated when endoplasmic reticulum-associated degradation (ERAD) is defective; however, the underlying mechanistic basis remains unclear. Based on a genome-wide CRISPR-Cas9 screen, we show that a widely expressed GPI-anchored protein CD55 precursor and ER-resident ARV1 are involved in upregulation of GPI biosynthesis under ERAD-deficient conditions. In cells defective in GPI transamidase, GPI-anchored protein precursors fail to obtain GPI, with the remaining uncleaved GPI-attachment signal at the C-termini. We show that ERAD deficiency causes accumulation of the CD55 precursor, which in turn upregulates GPI biosynthesis, where the GPI-attachment signal peptide is the active element. Among the 31 GPI-anchored proteins tested, only the GPI-attachment signal peptides of CD55, CD48, and PLET1 enhance GPI biosynthesis. ARV1 is prerequisite for the GPI upregulation by CD55 precursor. Our data indicate that GPI biosynthesis is balanced to need by ARV1 and precursors of specific GPI-anchored proteins.

Automated summary

Liu et al. demonstrate that precursors of specific GPI-anchored proteins, in collaboration with ER-resident ARV1, contribute to the upregulation of GPI biosynthesis. This study provides insights into the mechanism by which GPI biosynthesis is regulated.