A Golgi Lipid Signaling Pathway Controls Apical Golgi Distribution and Cell Polarity during Neurogenesis

Abstract

Phosphatidylinositol (PtdIns) transfer proteins (PITPs) stimulate PtdIns-4-P synthesis and signaling in eukaryotic cells, but to what biological outcomes such signaling circuits are coupled remains unclear. Herein, we show that two highly related StART-like PITPs, PITPNA and PITPNB, act in a redundant fashion to support development of the embryonic mammalian neocortex. PITPNA/PITPNB do so by driving PtdIns-4-P-dependent recruitment of GOLPH3, and likely ceramide transfer protein (CERT), to Golgi membranes with GOLPH3 recruitment serving to promote MYO18A- and F-actin-directed loading of the Golgi network to apical processes of neural stem cells (NSCs). We propose the primary role for PITP/PtdIns-4-P/GOLPH3/CERT signaling in NSC Golgi is not in regulating bulk membrane trafficking but in optimizing apically directed membrane trafficking and/or apical membrane signaling during neurogenesis.

Defining the Subcellular Distribution and Metabolic Channeling of Phosphatidylinositol

“…Interestingly, members of the StARkin-related and Sec14 domain-containing (CRAL-TRIO) superfamilies of LTPs have been classically defined as PtdIns-transfer proteins (PITPs) that are thought to function by redistributing PtdIns from donor to acceptor membranes, likely as part of a heterotypic exchange involving additional lipid species such as phosphatidylcholine or phosphatidic acid (Cockcroft and Carvou, 2007; Grabon et al, 2019). Despite their name, it is yet to be understood how these PITPs function within intact cells; although unique PITPs are increasingly linked to specific signaling modalities in studies of model organisms (Xie et al, 2018; Huang et al, 2018). In addition to the autonomous PITPs, recent work has also suggested that PtdIns can be used as a lipid cargo by the relatively promiscuous TUbular LIPid-binding (TULIP) family of LTPs that possess synaptotagmin-like mitochondrial lipid-binding protein (SMP) domains; including a report of preferential PtdIns transfer from the ER to the PM by the SMP domain-containing protein TMEM24 following PLC activation and PtdIns(4,5)P 2 hydrolysis (Lees et al, 2017).…”

The Glyco-enzyme adaptor GOLPH3 Links Intra-Golgi Transport Dynamics to Glycosylation Patterns and Cell Proliferation

“…Finally, also enzyme-unrelated activities of GOLPH3 have been proposed to contribute to its oncogenicity. Among these, the GOLPH3 effects on cargo export from the TGN, and on the DNA damage response have been thoroughly characterized (Dippold et al, 2009;Farber-Katz et al, 2014;Halberg et al, 2016;Rahajeng et al, 2019;Xie et al, 2018). It will be interesting to examine how these mechanisms synergize with the effects of GOLPH3 on GSL metabolism described in this study.…”

Direct trafficking pathways from the Golgi apparatus to the plasma membrane

“…As a result, depletion of Nir2 affects the transport of tsVSV-G from the trans-Golgi to the cell surface. Similarly, two other PI transfer proteins, PITPNA and PITPNB, stimulate the production of PI(4)P which promotes the recruitment of GOLPH3 and CERT to the Golgi thus facilitating the apical targeting of membrane trafficking in neural stem cells [191].…”