Phosphorylation of Tudor-SN, a novel substrate of JNK, is involved in the efficient recruitment of Tudor-SN into stress granules

Abstract

Posttranslational modifications of certain stress granule (SG) proteins are closely related to the assembly of SGs, a type of cytoplasmic foci structure. Our previous studies revealed that the Tudor staphylococcal nuclease (Tudor-SN) protein participates in the formation of SGs. However, the functional significance of potential Tudor-SN modifications during stress has not been reported. In this study, we demonstrated that the Tudor-SN protein was phosphorylated at threonine 103 (T103) upon stimulation with arsenite. In addition, c-Jun N-terminal kinase (JNK) was found to be responsible for Tudor-SN phosphorylation at the T103 site. We further illustrated that either a T103A mutation or the suppression of phosphorylation of T103 by the JNK inhibitor SP600125 inhibited the efficient recruitment of Tudor-SN into SGs. In addition, the T103A mutation could affect the physical binding of Tudor-SN with the G3BP (Ras-GAP SH3 domain-binding protein) protein but not with the HuR (Hu antigen R) protein and AGTR1-3'UTR (3'-untranslated region of angiotensin II receptor, type 1) mRNA cargo. These data suggested that JNK-enhanced Tudor-SN phosphorylation promotes the interaction between Tudor-SN and G3BP and facilitates the efficient recruitment of Tudor-SN into SGs under conditions of sodium arsenite-induced oxidative stress. This finding provides novel insights into the physiological function of Tudor-SN modification.

Aggregation of SND1 in Stress Granules is Associated with the Microtubule Cytoskeleton During Heat Shock Stimulus

“…Previously, we found that the SND1 protein can interact and colocalize with PABP1 and regulate the FRAP dynamics of G3BP‐tracing SGs in response to arsenite sodium‐mediated oxidative stress conditions (Gao et al, ). Very recently, we found that c‐Jun N‐terminal kinase (JNK) can increase the phosphorylation of SND1 at threonine 103 (T103), which is involved in the efficient aggregation of the SND1 protein into SGs (Su et al, ). Here, we found that the assembly of SND1 granules upon heat shock stimulus in HeLa cells occurs in a microtubule transport‐dependent manner.…”

The multifaceted oncogene SND1 in cancer: focus on hepatocellular carcinoma

“…Ras GTPase activating protein SH3 domain binding protein (G3BP) is a phosphorylation dependent endoribonuclease that assembles stress granules and potentially degrades the SG mRNAs. Under oxidative stress, c-JNK phosphorylates SND1 at threonine 103, promoting the binding of its SN domain with G3BP to form stress granules [48] . It is not yet clear if the role of SND1 is limited to assembling these SGs or extends beyond that where the endonuclease activity of SND1 participates in degrading SG mRNAs.…”

Global Tudor‐SN transgenic mice are protected from obesity‐induced hepatic steatosis and insulin resistance

“…Tudor-staphylococcal nuclease (SN), also known as staphylococcal nuclease domain containing 1 (Snd1), is a highly conserved and ubiquitously expressed multifunctional protein (15)(16)(17)(18)(19)(20)(21)(22)(23). This enzyme comprises a tandem repeat of 4 SN-like domains (referred to as SN domains) at the N terminus and a fusion of a Tudor domain with a partial SN domain at the C terminus (referred to as a TSN domain) (22).…”

“…This enzyme comprises a tandem repeat of 4 SN-like domains (referred to as SN domains) at the N terminus and a fusion of a Tudor domain with a partial SN domain at the C terminus (referred to as a TSN domain) (22). Tudor-SN is normally localized in the cytoplasm except under certain circumstances, such as stress, in which it may shuttle between the nucleus and the cytoplasm (16,19,23). This protein plays important roles in the early stage of the DNA damage response in a poly-ADP-ribosylation-dependent manner via interaction with poly (ADP-ribose) polymerase (Parp)-1 through an SN domain (23).…”