Trp-tRNA synthetase bridges DNA-PKcs to PARP-1 to link IFN-γ and p53 signaling

Sajish, Mathew; Zhou, Quansheng; Kishi, Shuji; Valdez, Delgado M.; Kapoor, Mili; Guo, Min; Lee, Sunhee; Kim, Sung Hoon; Yang, Xiang‐Lei; Schimmel, Paul

doi:10.1038/nchembio.937

Cited by 82 publications

(95 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to attaching Trp to its specific tRNA, which occurs mainly in the cytoplasm, WARS is involved in cellular signaling processes in the nucleus or in the extracellular space 21-24 . To investigate if Trp starvation affects WARS expression in specific cellular locations, we analyzed WARS protein expression in cytoplasmic and nuclear cell fractions (Figure 3F) as well as in cell supernatants (Figure 3G).…”

Section: Resultsmentioning

confidence: 99%

“…A truncated version of WARS is secreted in response to IFNγ and elicits angiostatic effects 23 through inhibition of endothelial cell-cell junctions 24 . Upon infection, monocytes secrete full-length WARS, which induces phagocytosis and chemokine production in macrophages 21 . We therefore tested if the upregulation of WARS in response to Trp shortage also increases extracellular WARS protein levels.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation

et al. 2018

View full text Add to dashboard Cite

Tryptophan (Trp) metabolism is an important target in immuno-oncology as it represents a powerful immunosuppressive mechanism hijacked by tumors for protection against immune destruction. However, it remains unclear how tumor cells can proliferate while degrading the essential amino acid Trp. Trp is incorporated into proteins after it is attached to its tRNA by tryptophanyl-tRNA synthestases. As the tryptophanyl-tRNA synthestases compete for Trp with the Trp-catabolizing enzymes, the balance between these enzymes will determine whether Trp is used for protein synthesis or is degraded. In human cancers expression of the Trp-degrading enzymes indoleamine-2,3-dioxygenase-1 (IDO1) and tryptophan-2,3-dioxygenase (TDO2) was positively associated with the expression of the tryptophanyl-tRNA synthestase WARS. One mechanism underlying the association between IDO1 and WARS identified in this study is their joint induction by IFNγ released from tumor-infiltrating T cells. Moreover, we show here that IDO1- and TDO2-mediated Trp deprivation upregulates WARS expression by activating the general control non-derepressible-2 (GCN2) kinase, leading to phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α) and induction of activating transcription factor 4 (ATF4). Trp deprivation induced cytoplasmic WARS expression but did not increase nuclear or extracellular WARS levels. GCN2 protected the cells against the effects of Trp starvation and enabled them to quickly make use of Trp for proliferation once it was replenished. Computational modeling of Trp metabolism revealed that Trp deficiency shifted Trp flux towards WARS and protein synthesis. Our data therefore suggest that the upregulation of WARS via IFNγ and/or GCN2-peIF2α-ATF4 signaling protects Trp-degrading cancer cells from excessive intracellular Trp depletion.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Collectively, these results suggested that regulation occurred due to negative feedback among TyrRS, PARP1, and SIRT1 under oxidative stress. In addition to their aminoacylation functions in protein synthesis, many aminoacyl-tRNA synthetases, including TyrRS, have been shown to take on multiple roles (41)(42)(43). Specifically, TyrRS was found to act as a sensor for oxidative stress after translocating to the nucleus, where it activates DNA damage repair genes that are downstream of E2F1 (7).…”

Section: Discussionmentioning

confidence: 99%

Acetylation promotes TyrRS nuclear translocation to prevent oxidative damage

Cao

Xiao

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Tyrosyl-tRNA synthetase (TyrRS) is well known for its essential aminoacylation function in protein synthesis. Recently, TyrRS has been shown to translocate to the nucleus and protect against DNA damage due to oxidative stress. However, the mechanism of TyrRS nuclear localization has not yet been determined. Herein, we report that TyrRS becomes highly acetylated in response to oxidative stress, which promotes nuclear translocation. Moreover, p300/ CBP-associated factor (PCAF), an acetyltransferase, and sirtuin 1 (SIRT1), a NAD + -dependent deacetylase, regulate the nuclear localization of TyrRS in an acetylation-dependent manner. Oxidative stress increases the level of PCAF and decreases the level of SIRT1 and deacetylase activity, all of which promote the nuclear translocation of hyperacetylated TyrRS. Furthermore, TyrRS is primarily acetylated on the K244 residue near the nuclear localization signal (NLS), and acetylation inhibits the aminoacylation activity of TyrRS. Molecular dynamics simulations have shown that the in silico acetylation of K244 induces conformational changes in TyrRS near the NLS, which may promote the nuclear translocation of acetylated TyrRS. Herein, we show that the acetylated K244 residue of TyrRS protects against DNA damage in mammalian cells and zebrafish by activating DNA repair genes downstream of transcription factor E2F1. Our study reveals a previously unknown mechanism by which acetylation regulates an aminoacyl-tRNA synthetase, thus affecting the repair pathways for damaged DNA.

show abstract

“…These domain additions are not needed for catalysis, but rather to endow the synthetases with functions beyond translation. These functions are associated with secreted, extracellular forms and with nuclear forms that are active in many different cell-signaling pathways (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). In addition, a recent study demonstrated that a novel domain, appended to SerRS at the time of the invertebrate to vertebrate transition, was essential for development of the closed vascular system (13).…”

mentioning

confidence: 99%

Regulated Capture by Exosomes of mRNAs for Cytoplasmic tRNA Synthetases

Wang

Zhou

et al. 2013

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background: Many tRNA synthetases (AARS) have extracellular and nuclear functions. Some of these functions might require the export of their mRNAs. Results: Packaging in exosomes of mRNAs for AARSs and a splice variant was demonstrated. Conclusion: Exosomes capture translation-competent AARS-derived mRNAs, which can be regulated by external stimuli. Significance: Exosomes are a source for extracellular distribution of AARS-derived RNA information.

show abstract

Trp-tRNA synthetase bridges DNA-PKcs to PARP-1 to link IFN-γ and p53 signaling

Cited by 82 publications

References 42 publications

Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation

Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation

Acetylation promotes TyrRS nuclear translocation to prevent oxidative damage

Regulated Capture by Exosomes of mRNAs for Cytoplasmic tRNA Synthetases

Contact Info

Product

Resources

About