期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：32
DOI：10.1073/pnas.2208317119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
During an animal’s life span, terminally differentiated cells must be resilient to fluctuating environmental and physiological stresses to assure proper function of a tissue and prevent disease. A key component of this resiliency is the maintenance of protein homeostasis. Our study reveals that the AMPylating enzyme filamentation induced by cyclic-AMP (Fic) is required in differentiated tissue for the regulation of the unfolded protein response (UPR) during both physiological and pharmacological stresses. We also propose that cells with high regenerative capacity may not require this level of regulation, as new cells will bypass the need for long-term survival. We predict that Fic is important in mitigating deleterious effects of UPR activation in a variety of tissues with UPR-associated diseases and thus holds promise as a new therapeutic target.
The proper balance of synthesis, folding, modification, and degradation of proteins, also known as protein homeostasis, is vital to cellular health and function. The unfolded protein response (UPR) is activated when the mechanisms maintaining protein homeostasis in the endoplasmic reticulum become overwhelmed. However, prolonged or strong UPR responses can result in elevated inflammation and cellular damage. Previously, we discovered that the enzyme filamentation induced by cyclic-AMP (Fic) can modulate the UPR response via posttranslational modification of binding immunoglobulin protein (BiP) by AMPylation during homeostasis and deAMPylation during stress. Loss of
fic in
Drosophila leads to vision defects and altered UPR activation in the fly eye. To investigate the importance of Fic-mediated AMPylation in a mammalian system, we generated a conditional null allele of
Fic in mice and characterized the effect of
Fic loss on the exocrine pancreas. Compared to controls,
Fic
−/−
mice exhibit elevated serum markers for pancreatic dysfunction and display enhanced UPR signaling in the exocrine pancreas in response to physiological and pharmacological stress. In addition, both
fic
−/−
flies and
Fic
−/−
mice show reduced capacity to recover from damage by stress that triggers the UPR. These findings show that Fic-mediated AMPylation acts as a molecular rheostat that is required to temper the UPR response in the mammalian pancreas during physiological stress. Based on these findings, we propose that repeated physiological stress in differentiated tissues requires this rheostat for tissue resilience and continued function over the lifetime of an animal.
关键词：enAMPylationFicunfolded protein responsepancreasER stress
