LysRS Serves as a Key Signaling Molecule in the Immune Response by Regulating Gene Expression

Yannay-Cohen, Nurit; Carmi-Levy, Irit; Kay, Gillian; Yang, Christopher Maolin; Han, Jung Min; Kemeny, David M.; Kim, Sung Hoon; Nechushtan, Hovav; Razin, Ehud

doi:10.1016/j.molcel.2009.05.019

Cited by 148 publications

(186 citation statements)

References 35 publications

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“…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.

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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.

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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.

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“…However, it has recently become clear that some human aaRSs also possess tissue-specific functions, distinct from their role in translation. Indeed, different aaRSs define pathways such as angiogenesis [TyrRS, TrpRS, and AIMP1 (44)(45)(46)], the immune response [LysRS (47)], inflammation [GluProRS (48)], apoptosis [GlnRS (49)], but also neural development [AIMP1, GlyRS, AIMP2 (50-52)], and tumorogenesis [LeuRS (53)]. The switch between the canonical aminoacylation function of an aaRS and other alternative functions might rely on a different process: (i) the oligomerization state, (ii) the subcellular localization, or (iii) the differential expression of the protein.…”

Section: A Previously Undescribed Model: Alternative Polyadenylation Ismentioning

confidence: 99%

Misfolded human tRNA isodecoder binds and neutralizes a 3′ UTR-embedded Alu element

Rudinger-Thirion

Lescure

Paulus

et al. 2011

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

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Several classes of small noncoding RNAs are key players in cellular metabolism including mRNA decoding, RNA processing, and mRNA stability. Here we show that a tRNA Asp isodecoder, corresponding to a human tRNA-derived sequence, binds to an embedded Alu RNA element contained in the 3′ UTR of the human aspartyl-tRNA synthetase mRNA. This interaction between two well-known classes of RNA molecules, tRNA and Alu RNA, is driven by an unexpected structural motif and induces a global rearrangement of the 3′ UTR. Besides, this 3′ UTR contains two functional polyadenylation signals. We propose a model where the tRNA/Alu interaction would modulate the accessibility of the two alternative polyadenylation sites and regulate the stability of the mRNA. This unique regulation mechanism would link gene expression to RNA polymerase III transcription and may have implications in a primate-specific signal pathway.aminoacyl-tRNA synthetase | posttranscriptional regulation A lu elements are the most abundant repetitive element in primate genomes. They belong to the short interspersed element family and are classified into subfamilies according to their appearance during evolution. Typically, there are more than 1 million Alu elements in a primate genome, which represents 10% of the genome overall. Modern Alu elements are about 300 base-pairs (bp) long and adopt a conserved structure composed of two similar, but distinct, domains (left and right arms) joined by an A-rich linker and followed by a short polyadenylation [poly (A)] stretch. Moreover, Alu elements are transcribed by RNA polymerase III (pol III), and Alu RNA transcripts are present in the cytosol of primate cells (1).Alu sequences are considered to be a huge reservoir of potential regulatory elements, which may have been involved in primate evolution and possibly facilitated their divergence from other mammals (2). Indeed, insertion of Alu elements could provide previously undescribed regulatory motifs to neighboring genes by creating previously undescribed transcription enhancers or promoters (3, 4). Alu elements can also modulate protein expression in a posttranscriptional way by at least two different mechanisms: (i) they are transcribed as free Alu RNA by the RNA PolIII, assembled into Alu ribonucleo-protein particles and act as transregulatory factors (2, 5, 6); or (ii) their transcription as a part of a mRNA will define them as cis-regulatory elements (7). If the Alu sequence is localized within the mRNA open reading frame, it can either affect gene expression by sequence disruption or, alternatively, simply add to the protein amino acid sequence (8). Nevertheless, most of the time they are present in 5′ and 3′ UTRs (2, 9, 10).Several reports indicate that mRNAs containing Alu elements in their 3′ UTRs are associated with cell growth and differentiation (11-15). Indeed, their presence could affect the processing of mRNAs at multiple levels (16). Specifically, they have been shown to modulate alternative splicing (e.g., ref. 17), RNA editing (e.g., ref. 18), nuclear ...

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“…We recently showed that LysRS, the main enzyme that produces Ap 4 A, translocates into the nucleus in activated mast cells (40). We hypothesized that Ap 4 A production occurs in the nuclei of activated mast cells, with concurrent Ap 4 A accumulation and LysRS nuclear localization.…”

Section: Ap 4 a Hydrolase Translocates Into The Nuclei Of Bmmcmentioning

confidence: 97%

Importin Beta Plays an Essential Role in the Regulation of the LysRS-Ap₄A Pathway in Immunologically Activated Mast Cells

Carmi-Levy¹,

Motzik²,

Ofir-Birin³

et al. 2011

Molecular and Cellular Biology

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LysRS Serves as a Key Signaling Molecule in the Immune Response by Regulating Gene Expression

Cited by 148 publications

References 35 publications

Acetylation promotes TyrRS nuclear translocation to prevent oxidative damage

Acetylation promotes TyrRS nuclear translocation to prevent oxidative damage

Misfolded human tRNA isodecoder binds and neutralizes a 3′ UTR-embedded Alu element

Importin Beta Plays an Essential Role in the Regulation of the LysRS-Ap₄A Pathway in Immunologically Activated Mast Cells

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LysRS Serves as a Key Signaling Molecule in the Immune Response by Regulating Gene Expression

Cited by 148 publications

References 35 publications

Acetylation promotes TyrRS nuclear translocation to prevent oxidative damage

Acetylation promotes TyrRS nuclear translocation to prevent oxidative damage

Misfolded human tRNA isodecoder binds and neutralizes a 3′ UTR-embedded Alu element

Importin Beta Plays an Essential Role in the Regulation of the LysRS-Ap4A Pathway in Immunologically Activated Mast Cells

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Importin Beta Plays an Essential Role in the Regulation of the LysRS-Ap₄A Pathway in Immunologically Activated Mast Cells