A model of secretory protein trafficking in recombinant AtT-20 cells

After their synthesis, secretory proteins in animal cells undergo a series of transport and processing steps before they are secreted. The amount and quality of protein obtained in culture medium depends on the rates of these intracellular steps. We present a model of recombinant protein trafficking in mouse pituitary AtT-20 cells based on currently available biological knowledge, plausible hypotheses, and quantitative secretion results, and we use it to simulate the dynamics of basal and induced secretion and to predict the dynamics of intracellular trafficking events. Besides the endoplasmic reticulum and Golgi, the model recognizes a conversion compartment (CC) where final processing of protein occurs, a storage compartment from which protein is secreted only in the presence of secretion stimulus, and constitutive and pseudoregulated (PR) pathways of secretion. The model further assumes that the protein flux is split between CC and PR and that the storage compartment exerts a negative feedback on protein flux through CC. The model predictions are compared with experimental results on secretion of human growth hormone (hGH) and insulin related peptides and on accumulation of hGH upon removal of secretion stimulus. The model is in agreement with data when either of two hypotheses is implemented: (a) cells always exhibit a high sorting efficiency at the trans-Golgi, but CC has the capacity to process only a fraction of the protein flux leaving the Golgi compartment; (b) the processing capacity of CC never becomes saturated, but significant missorting at the trans-Golgi occurs; in the case, the protein flux toward the plasma membrane becomes split both at the trans-Golgi cisternae and between CC and PR. The usefulness of the type of model considered in providing a quantitative description of intracellular events and in designing new experiments is discussed.