Stress granule and P-body clearance: Seeking coherence in acts of disappearance

Abstract

Stress granules and P-bodies are conserved cytoplasmic biomolecular condensates whose assembly and composition are well documented, but whose clearance mechanisms remain controversial or poorly described. Such understanding could provide new insight into how cells regulate biomolecular condensate formation and function, and identify therapeutic strategies in disease states where aberrant persistence of stress granules in particular is implicated. Here, I review and compare the contributions of chaperones, the cytoskeleton, post-translational modifications, RNA helicases, granulophagy and the proteasome to stress granule and P-body clearance. Additionally, I highlight the potentially vital role of RNA regulation, cellular energy, and changes in the interaction networks of stress granules and P-bodies as means of eliciting clearance. Finally, I discuss evidence for interplay of distinct clearance mechanisms, suggest future experimental directions, and suggest a simple working model of stress granule clearance.

Keywords: Chaperones; Cytoskeleton; G3BP; Granulophagy; MRNA; MRNA decay; P-bodies; Phosphorylation; Proteasome; RNA helicases; RNA modification; Stress Granules; Translation; Ubiquitination; VCP.

Figure 1:. Reported and putative means of SG clearance.

SG clearance is not fully understood, but multiple mechanisms have been reported including chaperone activity, cytoskeletal transport, RNA helicases, post-translational modifications (PTMs), granulophagy, proteasomal activity, and SG network disruption. Direct effects on SG-resident mRNA molecules have not been reported but are feasible given the multivalent, SG-scaffolding nature of mRNA and reported impacts of mRNA modification. A selection of examples of each clearance mechanism are depicted and identified in blue boxes; those with question marks are putative and/or not unambiguously demonstrated. Teal and orange objects with a yellow band indicate RNA-binding proteins with self-interacting domains (analogous to SG scaffolding proteins like G3BP1/2). “Helic.”, “Adap.” and “cap” refer to RNA helicases, VCP adaptor proteins, and network valency reducing, or “capping” proteins, respectively. Black arrows indicate a transition from one state to another, while red arrows/inhibitory lines indicate direct action of a protein or enzyme on a target with functional consequences. Dynamics, meaning the rate of mRNP entry and exit to/from SGs, and their fluidity, likely depends on ATP levels, which is required by almost all of the SG clearance mechanisms proposed. See main text for more details.