<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "STARD3: A Sphingolipid Transporter at Lysosome-ER Contact Sites"^^ . "Sphingolipid transport between organelles has been increasingly studied during the last \r\nyears, and a large body of evidence points to protein-mediated sphingolipid transfer at \r\norganelle contact sites. This is well characterized for sphingolipid transfer along the\r\nbiosynthetic pathway from the endoplasmic reticulum (ER) towards the plasma \r\nmembrane. However, the catabolic pathway is far less well studied. Here, a crucial but \r\nunexplored step is the recycling of the sphingosine backbone upon lysosomal \r\nsphingolipid degradation and its reintegration into the biosynthetic pathway at the ER. \r\nIn this study, I propose that the lysosomal cholesterol transporter STARD3 acts as a \r\nsphingosine transfer protein at lysosome-ER contact sites to facilitate sphingosine entry \r\ninto the recycling pathway.\r\nSTARD3 has been previously described to tether lysosomes to the ER via its FFAT motif \r\nthat binds to ER-resident proteins. At this contact, its START-domain transfers cholesterol \r\nfrom the ER to lysosomes to support endosome maturation and to maintain cholesterol \r\nlevels at the ER. I employed functionalized, photocrosslinkable sphingosine in intact cells \r\nto show that STARD3 also binds to sphingosine. Functionally, I could show that \r\noverexpression of STARD3 drives the sphingosine metabolism towards biogenesis of \r\nhigher sphingolipid species, such as sphingomyelin, while depleting cellular STARD3\r\nlevels results in a delayed sphingosine metabolism, which indicates STARD3 as a \r\nlysosomal sphingosine exporter. This transfer is dependent on a functional FFAT motif, \r\nconsistent with sphingosine transfer taking place at the lysosome-ER contact site.\r\nSTARD3 FFAT mutation or drug-induced prevention of sphingosine entry into the \r\nrecycling pathway switches the sphingolipid metabolism towards the degradation \r\npathway. Finally, molecular simulations, mutational analyses, and cholesterol \r\ncompetition studies revealed the START domain as a sphingosine transfer domain that \r\ncan either transfer cholesterol or sphingosine at lysosome-ER contact sites.\r\nOverall, I hypothesize that STARD3 transfers sphingosine from the lysosome towards the \r\nER along a subcellular lipid gradient, potentially in exchange for the transfer of \r\ncholesterol. As such, STARD3 is the first protein able to facilitate sphingosine exit from \r\nlysosomes towards other organelles. This represents an important connection between \r\nthe catabolic and anabolic sphingolipid pathways and has wide-ranging implications for \r\nfuture studies relating to lysosomal lipid efflux and sphingolipid-mediated processes in \r\nhealth and disease."^^ . "2022" . . . . . . . "Pia"^^ . "Hempelmann"^^ . "Pia Hempelmann"^^ . . . . . . "STARD3: A Sphingolipid Transporter at Lysosome-ER Contact Sites (PDF)"^^ . . . "Dissertation_Pia_Hempelmann.pdf"^^ . . . "STARD3: A Sphingolipid Transporter at Lysosome-ER Contact Sites (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "STARD3: A Sphingolipid Transporter at Lysosome-ER Contact Sites (Other)"^^ . . . . . . "preview.jpg"^^ . . . "STARD3: A Sphingolipid Transporter at Lysosome-ER Contact Sites (Other)"^^ . . . . . . "medium.jpg"^^ . . . "STARD3: A Sphingolipid Transporter at Lysosome-ER Contact Sites (Other)"^^ . . . . . . "small.jpg"^^ . . . "STARD3: A Sphingolipid Transporter at Lysosome-ER Contact Sites (Other)"^^ . . . . . . "indexcodes.txt"^^ . . "HTML Summary of #32058 \n\nSTARD3: A Sphingolipid Transporter at Lysosome-ER Contact Sites\n\n" . "text/html" . .