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：33
DOI：10.1073/pnas.2204235119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
The presence of dsRNA in the cytosol is a marker of infection and elicits an immune response. One aspect of this immune response is the activation of the eIF2α kinase PKR, which results in translational reprogramming and stress granule formation. Here, we show that dsRNA induces the formation of a novel condensate by PKR that is distinct from other known ribonucleoprotein assemblies. These results challenge prior observations that PKR is recruited to stress granules and suggest that the condensation of PKR may be a mechanism that cells use to modulate PKR activation.
Mammalian cells respond to dsRNA in multiple manners. One key response to dsRNA is the activation of PKR, an eIF2α kinase, which triggers translational arrest and the formation of stress granules. However, the process of PKR activation in cells is not fully understood. In response to increased endogenous or exogenous dsRNA, we observed that PKR forms novel cytosolic condensates, referred to as dsRNA-induced foci (dRIFs). dRIFs contain dsRNA, form in proportion to dsRNA, and are enhanced by longer dsRNAs. dRIFs enrich several other dsRNA-binding proteins, including ADAR1, Stau1, NLRP1, and PACT. Strikingly, dRIFs correlate with and form before translation repression by PKR and localize to regions of cells where PKR activation is initiated. We hypothesize that dRIF formation is a mechanism that cells use to enhance the sensitivity of PKR activation in response to low levels of dsRNA or to overcome viral inhibitors of PKR activation.
