Differences between acute and chronic stress granules, and how these differences may impact function in human disease

Abstract

Stress granules are macromolecular aggregates of mRNA and proteins assembling in response to stresses that promote the repression of protein synthesis. Most of the work characterizing stress granules has been done under acute stress conditions or during viral infection. Comparatively less work has been done to understand stress granule assembly during chronic stress, specifically regarding the composition and function of stress granules in this alternative context. Here, we describe key aspects of stress granule biology under acute stress, and how these stress granule hallmarks differ in the context of chronic stress conditions. We will provide perspective for future work aimed at further uncovering the form and function of both acute and chronic stress granules and discuss aspects of stress granule biology that have the potential to be exploited in human disease.

Fig. 1.

General features of acute stress granules. During unstressed conditions, mRNAs generally exist in a complex with ribosomes and translation initiation factors, as well as RNA binding proteins that stabilize the mRNA and promote its translation. During stress conditions, the cap-binding complex is disassembled or 40S ribosomes are stalled within the 5′UTR. Stress promotes disassembly of the cap-binding complex or inhibits 40S scanning via activation of 4EBPs, inhibition of EIF4A activity (iEIF4A), or inactivation of eIF2 by promoting eIF2α phosphorylation. Bound 80S ribosomes present within the open reading frame run off the mRNA under these conditions leaving exposed mRNA that collapses onto itself and is subject to RNA folding. At this point, RNA binding proteins also associate with the mRNA and the resulting complexes assemble into SG dependent on specific (A) and non-specific (B) protein:protein interactions requiring globular and disordered domains, respectively, as well as RNA:RNA interactions (C) resulting from free mRNA.

Fig. 2.

Acute and chronic SG differ in composition and effects on cell fate. Acute stress granules (left) contain many signaling components as well as 40S ribosomes, are very dynamic, and have a pro-survival function. In contrast, chronic SG (right) lack 40S ribosomes, are static and have a pro-death function. Components known to exist within each type of SG are listed (green, acute SG-specific; blue, present in both acute and chronic SG; red, chronic SG-specific).