Abstract
Phosphoinositides are key regulators of a large number of diverse cellular processes that include membrane trafficking, plasma membrane receptor signaling, cell proliferation, and transcription. How a small number of chemically distinct phosphoinositide signals are functionally amplified to exert specific control over such a diverse set of biological outcomes remains incompletely understood. To this end, a novel mechanism is now taking shape, and it involves phosphatidylinositol (PtdIns) transfer proteins (PITPs). The concept that PITPs exert instructive regulation of PtdIns 4-OH kinase activities and thereby channel phosphoinositide production to specific biological outcomes, identifies PITPs as central factors in the diversification of phosphoinositide signaling. There are two evolutionarily distinct families of PITPs: the Sec14-like and the StAR-related lipid transfer domain (START)-like families. Of these two families, the START-like PITPs are the least understood. Herein, we review recent insights into the biochemical, cellular, and physiological function of both PITP families with greater emphasis on the START-like PITPs, and we discuss the underlying mechanisms through which these proteins regulate phosphoinositide signaling and how these actions translate to human health and disease.
Highlights
Phosphoinositides are key regulators of a large number of diverse cellular processes that include membrane trafficking, plasma membrane receptor signaling, cell proliferation, and transcription
As the bulk of the evidence to date connects phosphatidylinositol transfer protein (PITP) function with PtdIns4P synthesis/signaling, we focus on PtdIns4P and the 4-OH phosphoinositide signaling in this review
The mechanisms through which the phosphoinositide code is functionally diversified are critical to cellular function as well as being of direct relevance to human health and disease
Summary
The discovery that Sec is the major yeast PITP [19], and subsequent studies demonstrating that Sec executes an essential coordination of multiple aspects of lipid metabolism to support membrane trafficking from the yeast trans-Golgi network (TGN) [20, 24], revealed for the first time that lipid signaling is a core feature of constitutive membrane trafficking in eukaryotic cells, as it relates to the Golgi system. Arf1-GTP cooperates with PtdIns4P to recruit vesicle biogenesis machinery that nucleates vesicle formation These factors include components of clathrin adaptor protein complex 1 (AP-1), Rab GTPases and Rab-guanine nucleotide exchange factors, oxysterol binding proteins (OSBPs), and effector proteins, such as the Gga Arf-GTPase-binding proteins that regulate trafficking between the TGN and lysosomes [81,82,83]. The functions of discrete PtdIns4P pools can be further specified by the local PtdIns4P concentration, such as in the activation of yeast Sec, a ras-like G-protein required for consumption of post-Golgi secretory vesicles at the plasma membrane. Basal PtdIns4P (as is presumably the prevailing condition on post-Golgi membranes) facilitates Sec binding to Sec for downstream activation of Sec, whereas elevated PtdIns4P promotes Sec binding to Golgi Ypt31 [89]
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