Noncanonical regulation of phosphatidylserine metabolism by a Sec14-like protein and a lipid kinase

Abstract

The yeast phosphatidylserine (PtdSer) decarboxylase Psd2 is proposed to engage in a membrane contact site (MCS) for PtdSer decarboxylation to phosphatidylethanolamine (PtdEtn). This proposed MCS harbors Psd2, the Sec14-like phosphatidylinositol transfer protein (PITP) Sfh4, the Stt4 phosphatidylinositol (PtdIns) 4-OH kinase, the Scs2 tether, and an uncharacterized protein. We report that, of these components, only Sfh4 and Stt4 regulate Psd2 activity in vivo. They do so via distinct mechanisms. Sfh4 operates via a mechanism for which its PtdIns-transfer activity is dispensable but requires an Sfh4-Psd2 physical interaction. The other requires Stt4-mediated production of PtdIns-4-phosphate (PtdIns4P), where Stt4 (along with the Sac1 PtdIns4P phosphatase and endoplasmic reticulum–plasma membrane tethers) indirectly modulate Psd2 activity via a PtdIns4P homeostatic mechanism that influences PtdSer accessibility to Psd2. These results identify an example in which the biological function of a Sec14-like PITP is cleanly uncoupled from its canonical in vitro PtdIns-transfer activity and challenge popular functional assumptions regarding lipid-transfer protein involvements in MCS function.

Lipid Metabolism at Membrane Contacts: Dynamics and Functions Beyond Lipid Homeostasis

“…In mammalian cells, ER-derived PS is rapidly converted to PE by decarboxylation and this is thought to take place in mitochondria only. However, yeast has two PS decarboxylases: mitochondrial Psd1 and the trans- Golgi network/endosomal Psd2 ( Wang et al, 2020 ). Psd2 is proposed to engage with MCSs for PS decarboxylation ( Wang et al, 2020 ).…”

“…However, yeast has two PS decarboxylases: mitochondrial Psd1 and the trans- Golgi network/endosomal Psd2 ( Wang et al, 2020 ). Psd2 is proposed to engage with MCSs for PS decarboxylation ( Wang et al, 2020 ). Several proteins are known to be required in conjunction with Psd2 for PS transport to occur, such as the sec14-like phosphatidylinositol transfer protein (PITP) Sfh4, the phosphatidylinositol 4-kinase (PI4K) Stt4, the tether Scs2, and an uncharacterized protein Pbi1 ( Wang et al, 2020 ; Figure 2C ).…”

“…Psd2 is proposed to engage with MCSs for PS decarboxylation ( Wang et al, 2020 ). Several proteins are known to be required in conjunction with Psd2 for PS transport to occur, such as the sec14-like phosphatidylinositol transfer protein (PITP) Sfh4, the phosphatidylinositol 4-kinase (PI4K) Stt4, the tether Scs2, and an uncharacterized protein Pbi1 ( Wang et al, 2020 ; Figure 2C ). A recent study demonstrated that Sfh4 affects Psd2 activity through direct physical interaction with Psd2 and the functional effect of Sfh4 is independent of its PI-binding/exchange activity ( Wang et al, 2020 ).…”

Lipid Exchangers: Cellular Functions and Mechanistic Links With Phosphoinositide Metabolism

“…Sfh4p functions in ER-endosome contact sites to activate the PS-to-PE conversion by Psd2p. Sfh4p interacts physically with Psd2p and is regulated by PI(4)P. It is unclear how PS is transferred to endosomes (Sfh4p does not transfer PS) and why Sfh4p has PI binding ability (Riekhof et al, 2014;Wang et al, 2020).…”

Tricalbin proteins regulate plasma membrane phospholipid homeostasis

“…Membrane contact sites between the ER and the PM, termed ER-PM contacts, are proposed to serve as integral sites for the coordinated regulation of lipid metabolism and transport (Pichler et al, 2001; Chang et al, 2017; Balla et al, 2020; Nishimura and Stefan, 2020). However, a strict requirement for ER-PM contacts in non-vesicular transport of lipids from the ER to PM has been recently questioned (Quon et al, 2018; Wang et al, 2020), necessitating further evaluation of the vital roles of ER-PM contacts, as well as the proteins proposed to form and function at these important cellular structures.…”