ADP ribosylation of BiP affords protection against misfolding while minimizing the cost of unfolded protein degradation in a kinetic model of the ER. (A) Time evolution of the concentration of U, UB, B, and Br over a 24-h period (at periodic steady state; see Fig 6) in a model ER that is unable (ADPr⁻) or able (ADPr⁺) to regulate BiP by ADP ribosylation. The bottom graph shows the diurnal variation in the synthesis of U in a hypothetical pancreatic cell (with a volume of 3×10⁻¹² L) of a mouse that fasts during the day and feeds at night. (B) Comparison of the time evolution of the rates of aggregation and degradation of unfolded protein in the ADPr⁻ and ADPr⁺ models. The red shading highlights surplus aggregation or degradation of unfolded proteins in the ADPr⁻ model. Note the dominance of the red trace in aggregation during the high-synthesis phase of the diurnal variation in translation (top) and in degradation during the low-synthesis phase of the cycle. The latent phase of the response of BiP synthesis to changes in the burden of unfolded proteins is indicated by the bar (t₀).