Poly(A)⁺ mRNA‐binding protein Tudor‐SN regulates stress granules aggregation dynamics

Abstract

Stress granules (SGs) and processing bodies (PBs) comprise the main types of cytoplasmic RNA foci during stress. Our previous data indicate that knockdown of human Tudor staphylococcal nuclease (Tudor-SN) affects the aggregation of SGs. However, the precise molecular mechanism has not been determined fully. In the present study, we demonstrate that Tudor-SN binds and colocalizes with many core components of SGs, such as poly(A) + mRNA binding protein 1, T-cell internal antigen-1-related protein and poly(A) + mRNA, and SG/PB sharing proteins Argonaute 1/2, but not PB core proteins, such as decapping enzyme 1 a/b, confirming that Tudor-SN is an SG-specific protein. We also demonstrate that the Tudor-SN granule actively communicates with the nuclear and cytosolic pool under stress conditions. Tudor-SN can regulate the aggregation dynamics of poly(A) + mRNA-containing SGs and selectively stabilize the SG-associated mRNA during cellular stress.

Polysomes, Stress Granules, and Processing Bodies: A Dynamic Triumvirate Controlling Cytoplasmic mRNA Fate and Function

“…Some RBPs are essential for SG formation in these species, such as T-cell-restricted intracellular antigen-1 (TIA-1) and TIA-1-related (TIAR) proteins (Gilks et al, 2004), Ras-GTPase-activating protein SH3-domain-binding proteins (G3BPs; Aulas et al, 2015), and Tudor staphylococcal nucleases (TSNs; Gao et al, 2015). Recent studies have revealed the roles of related proteins in plants ( Fig.…”

Tudor staphylococcal nuclease: biochemistry and functions

“…3 It has also been revealed that TSN is required for the proper aggregation and stabilization of poly(A) + mRNAs, such as those encoding AGTR1 and IGFBP2 (insulin-like growth factor-binding protein 2), in SGs during stress in mammals. 37 In plants, TSN was consistently shown to be required for stabilization of stress-responsive mRNAs under various experimental settings. 36,38,67 These findings demonstrate that TSN-dependent stabilization of specific mRNA molecules is crucial for stress adaptation.…”

“…Indeed, both animal and plant TSN proteins interact with several SGassociated proteins 11,12,35,36 and control the fate (stabilization or degradation) of specific mRNAs during stress. 10,[36][37][38] However, lineage-specific intracellular localization of TSN raises doubts about cross-kingdom conservation of all TSN functions. For example, unlike nuclear-cytoplasmic localization of TSN in animal cells, plant TSN is exclusively cytoplasmic, indicating that the probability of its involvement in transcriptional regulation and splicing in plants is low.…”

“…63,64 Notably, TSN has been found to interact with Ago1 and Ago2 in B. mori and mammals, with ADAR1 and G3BP in mammalian cells and with the calmodulin-like protein 38 (CML38) in Arabidopsis thaliana (Figure 4; pathway 6). 11,12,22,35,37 Experimental evidence indicates that TSN may act as a scaffolding factor recruiting other proteins to the cytoplasmic foci. 10 In this context, one can also speculate that TSN might sequester different proteins into SGs thus repressing their physiological function.…”

“…65,66 Accordingly, TSN as a SG-associated protein appears to have an essential role in binding and stabilization of specific mRNAs during stress in mammals and plants (Figure 4; pathway 7). [36][37][38] TSNmediated mRNA stabilization was shown to be accompanied by enhanced translational efficiency of AGTR1 (angiotensin II receptor, type 1 mRNA), resulting in an elevated protein levels. 3 It has also been revealed that TSN is required for the proper aggregation and stabilization of poly(A) + mRNAs, such as those encoding AGTR1 and IGFBP2 (insulin-like growth factor-binding protein 2), in SGs during stress in mammals.…”