A retrospective on phosphatidylinositol transfer proteins (PITPs) – A fifty-year journey

This retrospective traces the evolution of our understanding of the phosphatidylinositol transfer protein (PITP) family over the past fifty years, beginning with its purification. I summarise the early identification of PITPs as phosphatidylinositol/phosphatidylcholine (PI/PC) transfer proteins and describe how the conserved PITP domain was subsequently recognised in five mammalian proteins, occurring either as a single domain or within a multi-domain architecture. Parallel genetic studies in Drosophila led to the discovery of RdgB, a retinal degeneration mutant protein containing a PITP domain. Later work revealed that some members of the PITP family members mediate PI/PA (phosphatidate) exchange enabling the reciprocal transfer of PA and PI during phospholipase C (PLC) signalling. PITPs thus function as key lipid exchangers, delivering PI for synthesis of phosphorylated derivatives including phosphatidylinositol 4-phosphate (PI4P) and phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P₂) across cellular compartments. These activities position PITPs at the core of fundamental processes such as PLC signalling and Golgi membrane trafficking, where phosphoinositides play central regulatory roles. Finally, I highlight how PITPs have emerged as critical factors in diverse physiological processes and as contributors to a growing range of pathological conditions.