Abstract
ABSTRACTMembrane lipid biosynthesis is a complex process that takes place in various intracellular compartments. Glycosylphosphatidylinositol (GPI), a lipid involved in membrane anchoring of some proteins, is synthesized by the PIG enzymes. Most PIGs are localized to the endoplasmic reticulum (ER), but Drosophila PIG-B (DmPIG-B) is localized to the nuclear envelope (NE). To determine whether the NE localization of DmPIG-B is functionally important, we defined the determinants of localization and generated an ER-localized form, denoted DmPIG-B[ER]. The enzymatic activity of DmPIG-B[ER] was comparable to that of NE-localized DmPIG-B[NE]. Expression of DmPIG-B[ER] inefficiently rescued the lethality of the PIG-B mutant, whereas DmPIG-B[NE] rescued this lethality fully. DmPIG-B[ER] was preferentially degraded by lysosomes, suggesting that the NE localization is essential for function and stability of the protein. In addition, we found that the region of the ER proximal to the NE is the site of translation of GPI-anchored proteins and addition of GPI. Thus, the NE and proximal ER may provide a platform for efficient GPI anchoring.
Highlights
Membrane lipid metabolism takes place in various cellular compartments, including the endoplasmic reticulum (ER), mitochondria, Golgi and endosomes
The rescue efficiency of DmPIG-B[nuclear envelope (NE)] was significantly higher than that of DmPIG-B[ER]. These results suggest that NE localization is essential for the function and stability of DmPIG-B
DmPIG-B localizes to the NE Seventeen enzymes involved in synthesis of GPI from phosphatidylinositol have been identified in mammals (Fig. 1A)
Summary
Membrane lipid metabolism takes place in various cellular compartments, including the endoplasmic reticulum (ER), mitochondria, Golgi and endosomes. The lipid glycosylphosphatidylinositol (GPI) is used as a membrane anchor for multiple cellular proteins. GPI-anchored proteins play important roles in development, immunity, neural functions and physiological homeostasis. Defects in GPI-anchor formation cause diseases such as paroxysmal nocturnal hemoglobinuria and inherited GPI deficiency (Almeida et al, 2009; Nishimura et al, 1999). GPI is synthesized from phosphatidylinositol in a multi-step reaction catalyzed by PIG enzymes (Kinoshita and Fujita, 2016). 17 enzymes have been identified in mammals (Fig. 1A) (Kinoshita, 2014).
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