FicD sensitizes cellular response to glucose fluctuations in mouse embryonic fibroblasts

• 成果类型: Article
• 署名作者: Gulen, Burak; Blevins, Aubrie; Kinch, Lisa N.; Servage, Kelly A.; Stewart, Nathan M.; Gray, Hillery F.; Casey, Amanda K.; Orth, Kim
• 署名单位: University of Texas System; University of Texas Southwestern Medical Center; Howard Hughes Medical Institute; University of Texas System; University of Texas Southwestern Medical Center
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9504
• DOI: 10.1073/pnas.2400781121
• 发表日期: 2024-09-17
• 关键词: unfolded protein response; endoplasmic-reticulum; stress; PATHWAY; ampylation; chaperone; domain; bip; proliferation; induction

摘要

During homeostasis, the endoplasmic reticulum (ER) maintains productive transmembrane and secretory protein folding that is vital for proper cellular function. The ER- resident HSP70 chaperone, binding immunoglobulin protein (BiP), plays a pivotal role in sensing ER stress to activate the unfolded protein response (UPR). BiP function is regulated by the bifunctional enzyme filamentation induced by cyclic- AMP domain protein (FicD) that mediates AMPylation and deAMPylation of BiP in response to changes in ER stress. AMPylated BiP acts as a molecular rheostat to regulate UPR signaling, yet little is known about the molecular consequences of FicD loss. In this study, we investigate the role of FicD in mouse embryonic fibroblast (MEF) response to pharmacologically and comparing robust chemical ER stress inducers to physiological glucose starvation stress and recovery. Wildtype MEFs respond to pharmacological ER stress by down- regulating stress recovery, and the maintenance of secretory protein homeostasis.