Functional Roles of Poly(ADP-Ribose) in Stress Granule Formation and Dynamics

Abstract

Stress granules (SGs) are highly dynamic cytoplasmic foci formed in response to stress. The formation of SGs is reported to be regulated by diverse post-translational protein modifications (PTMs). Among them, ADP-ribosylation is of emerging interest due to its recently identified roles in SG organization. In this review, we summarized the latest advances on the roles of poly(ADP-ribose) (PAR) in the regulation of SG formation and dynamics, including its function in modulating nucleocytoplasmic trafficking and SG recruitment of SG components, as well as its effects on protein phase separation behavior. Moreover, the functional role of PAR chain diversity on dynamic of SG composition is also introduced. Potential future developments on investigating global ADP-ribosylation networks, individual roles of different PARPs, and interactions between ADP-ribosylation and other PTMs in SGs are also discussed.

Keywords: PAR-binding; liquid–liquid phase separation; poly(ADP-ribose); post-translational modification; stress granules.

FIGURE 1

Roles of poly(ADP-ribose) (PAR) in stress granules (SG) formation, composition, and dynamics. When cells are exposed to stress, nuclear and cytoplasmic PARPs are activated, resulting in increased PAR chains with different lengths and structures. But how the PAR chains shuttle between the nucleus and the cytoplasm remains unclear. Formation of PAR chains is mediated through MAR, which might be a rate-limiting step. MAR-adding PARPs may act synergistically with PAR-adding PARPs to regulate stress granule formation. PARylated proteins or proteins bound to PARylated substrates are recruited to the specific sites where SG formation occurs and where they induce liquid-liquid phase separation. Diverse PAR chains contribute to diverse protein-protein and protein-RNA interactions. Once the stress is removed, PAR is degraded by PARG and the SGs are disassembled. However, if cells are exposed to long-term stress or PAR levels are mis-regulated, phase separated proteins are converted into protein aggregates and aberrant pathogenic SGs are formed.