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N-terminomics upon Arginyl-tRNA synthetase knock down

ABSTRACT: Arginine is associated with inflammation, cancer, and amino acid signaling, in part through the mTORC1 pathway. In cell-based assays and in the mouse, we found that arginine regulates nuclear levels of arginyl-tRNA synthetase (ArgRS), and that arginine depletion and inflammation reduced nuclear ArgRS in vivo. In the nucleus, ArgRS interacted and co-localized with the spliceosomal Serine/Arginine Repetitive Matrix Protein 2 (SRRM2) that is crucial for the formation of nuclear speckle condensates. ArgRS mRNA silencing changed specific splice junction usages, and these inversely correlated with SRRM2-induced usage changes of the same junctions. The prominently affected genes encompassed components of the mTORC1 pathway and showed ArgRS, arginine, and SRRM2 are tied together as upstream regulators of nuclear condensate trafficking related to the physiological response to inflammatory injury. This study is the first to demonstrate a regulatory role for an aaRS in shaping nuclear condensate dynamics and RNA splicing.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hepatocyte

DISEASE(S): Liver Cancer

SUBMITTER: Haissi Cui

LAB HEAD: Paul Schimmel

PROVIDER: PXD024091 | Pride | 2023-04-14

REPOSITORIES: Pride

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			Action	DRS
	20190721_PSHC-65-1.raw	Raw
	20190721_PSHC-65-2.raw	Raw
	20190721_PSHC-65-3.raw	Raw
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	20190721_PSHC-65-5.raw	Raw

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ArgRS, MetRS, and SRRM2 dependent changes in mRNA splicing and exon usage

Project description:Arginine is involved in inflammation and amino acid signaling, in part through the mTORC1 pathway. In cell-based assays and in the mouse, we found that arginine regulates nuclear levels of arginyl-tRNA synthetase (ArgRS) and that nuclear ArgRS interacts and co-localizes with the Serine/Arginine Repetitive Matrix Protein 2 (SRRM2), a spliceosomal protein crucial for the formation of nuclear speckle condensates. Arginine depletion or ArgRS knock down, both of which decreased nuclear ArgRS levels, mobilized SRRM2 for trafficking from nuclear condensates and altered mRNA processing and splice junction usage while minimally affecting expression of other cellular RNAs. These splice junction changes included a subset that were inversely correlated with SRRM2 knock down induced changes and the affected genes encompassed components of the mTORC1 pathway. This inverse correlation suggests that the nuclear ArgRS-SRRM2 interaction regulates SRRM2 nuclear trafficking and alternative splicing in the physiological response to changed arginine levels resulting from inflammation.

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