Figure 1

Model of molecular interactions at the TGN, comprising the key proteins PKD, PI4KIII β and CERT. Chemical conversions and changes of locations are represented by solid edges with number labels. Catalytic reactions and effective regulatory influences are represented by dashed edges. PKD and PI4KIII β are present as inactive or active TGN bound forms (variables PKD, PKDpDAG, PI4KIII β and PI4KIII βp, respectively). Active TGN bound PKD activates PI4KIII β (R1) and detaches CERT from the TGN membrane (R2) via phosphorylation (R3). Active PI4KIII β attracts CERT to the TGN (R5) by producing PI4P (R4). Two alternatives for CERT dependent ceramide transport are depicted. (A) In model A, ceramide transfer is ensured by a circular reaction scheme of CERT: Unphosphorylated CERT that is bound to both membranes (CERTaTGN) can deliver ceramide to the TGN (R10). Extraction of new ceramide requires detachment from the TGN (R3) via phosphorylation (CERTpER) and subsequent dephosphorylation (R9) at the ER (CERTaER). Thereby, PKD induced CERT phosphorylation (R2) and ceramide transfer (R10) dependent PKD activation (R8) constitute a positive feedback mechanism (R6, R7, R8, R2, R10), indicated by blue arrows. (B) In model B, unphosphorylated CERT (CERTa) is only transport-active in an ER-TGN double bound state (CERTaERTGN), constantly transferring ceramide (R10). Here, CERT phosphorylation (CERTp) (R3) causes an interruption of the transfer process and forms a negative feedback between PKD and CERT (R6, R7, R8, R2, R10), indicated by blue arrows.