Commentary for: A lipid scramblase TMEM41B is involved in the processing and transport of GPI-anchored proteins

• Published in: Journal of biochemistry (Tokyo) 2024-12
• Main Author: Hirayama, Hiroto
• Format: Article
• Language: English
• ISSN: 0021-924X; 1756-2651; 1756-2651
• DOI: 10.1093/jb/mvae085

Glycosylphosphatidylinositol (GPI) anchoring is a conserved post-translational modification in eukaryotes. This modification allows acceptor proteins to be expressed at the cell surface as GPI-anchored proteins (GPI-APs), which play critical roles in various biological processes. It has been proposed that remodeling of GPI after transferring acceptor proteins, including the PGAP1-dependent deacylation of GPI-inositol, functions as a checkpoint for transporting mature GPI-APs from the ER to the Golgi. A previous study identified several factors involved in regulating PGAP1-dependent GPI-inositol deacylation, including proteins associated with the calnexin cycles, SELT, and CLPTM1. A recent report by Cao et al., revealed that the loss of TMEM41B, an ER-resident lipid scramblase, rescues the defect in GPI-inositol deacylation in SELT-KO cells. Further investigation demonstrated that TMEM41B is essential for the efficient transport of both GPI-APs and transmembrane proteins from the ER to the Golgi. The study also found that PGAP1 proteins accumulate in the ER of TMEM41B-KO cells, suggesting that perturbations in the ER-membrane lipid integrity stabilize PGAP1 proteins, thereby enhancing the PGAP1 activity within the ER. These findings highlight that defects in TMEM41B impact two distinct processes: (i) the transport of GPI-APs from the ER to the Golgi, and (ii) the deacylation of GPI-APs.