FicD regulates adaptation to the unfolded protein response in the murine liver

Abstract

The unfolded protein response (UPR) is a cellular stress response that is activated when misfolded proteins accumulate in the endoplasmic reticulum (ER). Regulation of the UPR response must be adapted to the needs of the cell as prolonged UPR responses can result in disrupted cellular function and tissue damage. Previously, we discovered that the enzyme FicD (also known as Fic or HYPE) through its AMPylation and deAMPylation activity can modulate the UPR response via post-translational modification of BiP. FicD AMPylates BiP during homeostasis and deAMPylates BiP during stress. We hypothesized that FicD regulation of the UPR will play a role in mitigating the deleterious effects of UPR activation in tissues with frequent physiological stress. Here, we explore the role of FicD in the murine liver. As seen in our pancreatic studies, livers lacking FicD exhibit enhanced UPR signaling in response to short term physiologic fasting and feeding stress. However, in contrast to studies on the pancreas, livers, as a more regenerative tissue, remained remarkably resilient in the absence of FicD. The livers of FicD^−/− did not show marked changes in UPR signaling or damage after either chronic high fat diet (HFD) feeding or acute pathological UPR induction. Intriguingly, FicD^−/− mice showed changes in UPR induction and weight loss patterns following repeated pathological UPR induction. These findings indicate that FicD regulates UPR responses during mild physiological stress and in adaptation to repeated stresses, but there are tissue specific differences in the requirement for FicD regulation.