PtdIns4P exchange at endoplasmic reticulum-autolysosome contacts is essential for autophagy and neuronal homeostasis.

ABSTRACT

Inter-organelle contacts enable crosstalk among organelles, facilitating the exchange of materials and coordination of cellular events. In this study, we demonstrated that, upon starvation, autolysosomes recruit Pi4KIIα (Phosphatidylinositol 4-kinase II α) to generate phosphatidylinositol-4-phosphate (PtdIns4P) on their surface and establish endoplasmic reticulum (ER)-autolysosome contacts through PtdIns4P binding proteins Osbp (Oxysterol binding protein) and cert (ceramide transfer protein). We found that the Sac1 (Sac1 phosphatase), Osbp, and cert proteins are required for the reduction of PtdIns4P on autolysosomes. Loss of any of these proteins leads to defective macroautophagy/autophagy and neurodegeneration. Osbp, cert, and Sac1 are required for ER-Golgi contacts in fed cells. Our data establishes a new mode of organelle contact formation - the ER-Golgi contact machinery can be reused by ER-autolysosome contacts by re-locating PtdIns4P from the Golgi apparatus to autolysosomes when faced with starvation.Abbreviations Atg1 Autophagy-related 1; Atg8 Autophagy-related 8; Atg9 Autophagy-related 9; Atg12 Autophagy-related 12; cert ceramide transfer protein; Cp1/CathL cysteine proteinase-1; CTL control; ER endoplasmic reticulum; ERMCS ER-mitochondria contact site; fwd four wheel drive; GM130 Golgi matrix protein 130 kD; Osbp Oxysterol binding protein; PG phagophore; PtdIns4K phosphatidylinositol 4-kinase; Pi4KIIα Phosphatidylinositol 4-kinase II α; Pi4KIIIα Phosphatidylinositol 4-kinase III α; PtdIns4P phosphatidylinositol-4-phosphate; PR photoreceptor cell; RT room temperature; Sac1 Sac1 phosphatase; Stv starvation; Syx17 Syntaxin 17; TEM transmission electron microscopy; VAP VAMP-associated protein.