PKR: A Kinase to Remember

Abstract

Aging is a major risk factor for many diseases including metabolic syndrome, cancer, inflammation, and neurodegeneration. Identifying mechanistic common denominators underlying the impact of aging is essential for our fundamental understanding of age-related diseases and the possibility to propose new ways to fight them. One can define aging biochemically as prolonged metabolic stress, the innate cellular and molecular programs responding to it, and the new stable or unstable state of equilibrium between the two. A candidate to play a role in the process is protein kinase R (PKR), first identified as a cellular protector against viral infection and today known as a major regulator of central cellular processes including mRNA translation, transcriptional control, regulation of apoptosis, and cell proliferation. Prolonged imbalance in PKR activation is both affected by biochemical and metabolic parameters and affects them in turn to create a feedforward loop. Here, we portray the central role of PKR in transferring metabolic information and regulating cellular function with a focus on cancer, inflammation, and brain function. Later, we integrate information from open data sources and discuss current knowledge and gaps in the literature about the signaling cascades upstream and downstream of PKR in different cell types and function. Finally, we summarize current major points and biological means to manipulate PKR expression and/or activation and propose PKR as a therapeutic target to shift age/metabolic-dependent undesired steady states.

Protein kinase R and its cellular regulators in cancer: An active player or a surveillant?

“…Nevertheless, PKR still occupies a unique position at the crossroad of viral infection, cellular stresses, inflammation, and cell death/survival. As can be seen from its fundamental roles, PKR should be strictly controlled by cellular factors and its dysregulation is implicated in diverse pathological conditions such as infectious diseases, cancer, neurodegenerative disorders, and metabolic syndromes (reviewed in Gal‐Ben‐Ari, Barrera, Ehrlich, and Rosenblum ()). In this review, we will introduce cellular proteins and RNAs that regulate PKR activity.…”

“…PKR is implicated in other pathological condition such as inflammatory diseases, metabolic diseases, and neurological disorders (Gal‐Ben‐Ari et al, ). PKR activation is seen in Alzheimer's disease, Parkinson's disease, Huntington's disease, dementia, obesity, insulin resistance related to diabetes, etc.…”

Differential RNA editing between epithelial and mesenchymal tumors impacts mRNA abundance in immune response pathways

“…ILF3 was identified as a PKR substrate and serves as a negative regulator of viral replication upon phosphorylation 76,77 . Upon viral infection and sensing viral dsRNA, PKR activates, suppresses translation, and promotes apoptosis of affected cells 61 . Importantly, this mechanism has been targeted in oncolytic virotherapy for cancer.…”

“…6D). Activated by dsRNA, PKR suppresses translation and promotes apoptosis through its phosphorylation activity 60,61 . PKR also regulates various signaling pathways, such as NF-kB and p38 MAPK, in response to cellular stress 60 .…”

Avian Pattern Recognition Receptor Sensing and Signaling

“…Protein kinase R is a dsRNA sensor that is expressed at lower levels in normal cells but highly expressed in IFN-stimulated cells as an ISG. Upon viral dsRNA binding, activated PKR is a multifunctional protein that regulates translation, apoptosis, stress responses, metabolism, and NFκB/IRF3-dependent and -independent signaling [144]. The domain architecture of PKR consists of an N-terminal dsRNA binding domain composed of two tandem repeats of a conserved dsRNA binding motif 1 and 2, (dsRBM 1 and 2) interspaced by a linker and followed by a flexible linker connected to a C-terminal kinase domain [144].…”