Autoacetylation of NAT10 is critical for its function in rRNA transcription activation

Cai, Shi‐Ying; Liu, Xiaofeng; Zhang, Chunfeng; Xing, Baocai; Du, Xiaojuan

doi:10.1016/j.bbrc.2016.12.092

Cited by 46 publications

(36 citation statements)

References 38 publications

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“…Together, these results suggest that NAT10 inhibits autophagy induction independent of p53. To rule out the off-targeting effect of NAT10 siRNAs, we analyzed the autophagy levels in Cas9-edited HCT116-NAT10 KO cells ( 22 , 26 ). LC3-II accumulation was increased in HCT116-NAT10 KO cells, while this effect was reversed by ectopic Flag-NAT10 expression, confirming that NAT10 inhibits autophagy under normal conditions (Figure 2F ).…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, SIRT7 is released from the nucleoli, resulting in hyperacetylation of U3-55k and attenuation of pre-rRNA processing ( 50 ). As a nucleolar acetyltransferase, NAT10 contributes to rRNA biogenesis by promoting UBF1 acetylation and facilitating 18S rRNA processing ( 18 , 19 ), and autoacetylation of NAT10 is required for NAT10’s ability to promote rRNA biogenesis ( 22 ). However, whether the acetylation of NAT10 is regulated during energy stress remains unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, NAT10 is involved in rRNA processing by binding and acetylating rRNA ( 19–21 ). Recently, we found that the autoacetylation of NAT10 at K426 is required for its ability to activate rRNA biogenesis, and NAT10 is deacetylated in cells by Sirtuins ( 22 ). However, which member of the Sirtuin family regulates NAT10 acetylation and whether deacetylation of NAT10 regulates its biological function in rRNA biogenesis remain unknown.…”

Section: Introductionmentioning

confidence: 99%

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Deacetylation of NAT10 by Sirt1 promotes the transition from rRNA biogenesis to autophagy upon energy stress

Liu

Cai

Zhang

et al. 2018

Nucleic Acids Research

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Anabolism and catabolism are tightly regulated according to the cellular energy supply. Upon energy stress, ribosomal RNA (rRNA) biogenesis is inhibited, and autophagy is induced. However, the mechanism linking rRNA biogenesis and autophagy is unclear. Here, we demonstrate that the nucleolar protein NAT10 plays a role in the transition between rRNA biogenesis and autophagy. Under normal conditions, NAT10 is acetylated to activate rRNA biogenesis and inhibit autophagy induction. Mechanistic studies demonstrate that NAT10 binds to and acetylates the autophagy regulator Che-1 at K228 to suppress the Che-1-mediated transcriptional activation of downstream genes Redd1 and Deptor under adequate energy supply conditions. Upon energy stress, NAT10 is deacetylated by Sirt1, leading to suppression of NAT10-activated rRNA biogenesis. In addition, deacetylation of NAT10 abolishes the NAT10-mediated transcriptional repression of Che-1, leading to the release of autophagy inhibition. Collectively, we demonstrate that the acetylation status of NAT10 is important for the anabolism-catabolism transition in response to energy stress, providing a novel mechanism by which nucleolar proteins control rRNA synthesis and autophagy in response to the cellular energy supply.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Deacetylation of NAT10 by Sirt1 promotes the transition from rRNA biogenesis to autophagy upon energy stress

Liu

Cai

Zhang

et al. 2018

Nucleic Acids Research

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“…In addition to the Arg-GlcNAcylation of host death domain-containing proteins, we also observed the auto-arginine-GlcNAcylation of NleB, SseK1, and SseK3 by measuring total molecular weight by mass spec. Auto-modification of enzymes catalyzing post translational modifications usually played a significant role in self-activation, and it was indispensable in signaling transductions, such as autophosphorylation (35)(36)(37)(38) and autoacetylation (39)(40)(41)(42)(43)(44)(45).…”

Section: Ssek1 Rather Than Ssek3 Inhibits Tradd-activated Nf-κb and Cmentioning

confidence: 99%

Arginine-GlcNAcylation of death domain and NleB/SseK proteins is crucial for bacteria pathogenesis by regulating host cell death

Xue

Xing

et al. 2019

Preprint

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Death receptor signaling is critical for cell death, inflammation, and immune homeostasis. Hijacking death receptors and their corresponding adaptors through type III secretion system (T3SS) effectors has been evolved to be a bacterial evasion strategy. NleB from enteropathogenic Escherichia coli (EPEC) and SseK1/2/3 from Salmonella enterica serovar Typhimurium (S. Typhimurium) can modify some death domains involved in death receptor signaling through arginine-GlcNAcylation. This study applied a limited substrate screen from 12 death domain proteins with conserved arginines during EPEC and Salmonella infection and found that NleB from EPEC hijacked death receptor signaling tumor necrosis factor receptor 1 (TNFR1)-associated death domain protein (TRADD), FAS-associated death domain protein (FADD), and receptor-interacting serine/threonine-protein kinase 1 (RIPK1), whereas SseK1 and SseK3 disturbed TNFR signaling through the modification of TRADD Arg235/245 and TNFR1 Arg376, respectively. SseK1 and SseK3 delivered by Salmonella inhibited TNF-α- but not TNF-related apoptosis-inducing ligand (TRAIL)-induced cell death, which was consistent with their host substrate recognition specificity. Taking advantage of the substrate specificity of SseK effectors, we found that only SseK1 fully rescued the bacteria colonization deficiency contributed by NleBc in Citrobacter rodentium infection animal model, indicating that TRADD was likely to be the preferred in vivo substrate corresponding to NleB/SseK1-induced bacterial virulence. Furthermore, novel auto-arginine-GlcNAcylation was observed in NleB and SseK1/3, which promoted the enzyme activity. These findings suggest that arginine-GlcNAcylation in death domains and auto-arginine-GlcNAcylation catalyzed by type III-translocated bacterial effector proteins NleB/SseKs are crucial for bacteria pathogenesis in regulating nuclear factor-κB (NF-κB) and death receptor signaling pathways. This study provides an insight into the mechanism by which EPEC and Salmonella manipulate death receptor signaling and evade host immune defense through T3SS effectors.Author SummaryEnteropathogenic Escherichia coli (EPEC) and Salmonella enterica serovar Typhimurium (S. Typhimurium) are important food-borne pathogens infecting the intestine. They deliver type III secretion system effector NleB/SseKs to modify host death domain proteins by arginine GlcNAcylation. We screened the modification of 12 death domains containing conserved arginine in human genome by NleB, SseK1, SseK2, and SseK3 through ectopic co-expression and bacterial infection. Unlike multiple death receptor signaling inhibition by NleB, we found that SseK1 and SseK3 specifically hijacked tumor necrosis factor receptor 1 (TNFR1)-mediated death signaling through targeting TNFR1-associated death domain protein (TRADD) and receptor TNFR1, respectively. We identified the modification sites and suggested that TRADD was the in vivo target of NleB in mice infection model by utilizing the substrate specificity of SseK1 and SseK3, which highlighted anti-bacterial infection role of TRADD in death receptor signaling and non-death receptor signaling. In addition to the modification on host death domain substrates, we firstly elucidated the effect of auto-modification of the arginine GlcNAc transferases on the enzymatic activity, which widened our understanding of the newly discovered post translational modification in the process of pathogen-host interaction.

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“…N -acetyltransferase 10 (NAT10), a member of GCN5-related N -acetyltransferases (GNAT), has been reported to be involved in the regulation of ribosome biogenesis, histone acetylation, DNA damage response, microtubule reorganization, and cell cycle progression [ 1 , 2 , 3 , 4 ]. The expression of NAT10 is reported to increase in response to DNA damage, and ectopic expression of NAT10 maintains cell survival upon DNA damage stress [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of NAT10 Suppresses Melanogenesis and Melanoma Growth by Attenuating Microphthalmia-Associated Transcription Factor (MITF) Expression

Lee

Lim

et al. 2017

IJMS

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N-acetyltransferase 10 (NAT10) has been considered a target for the treatment of human diseases such as cancer and laminopathies; however, its functional role in the biology of melanocytes is questionable. Using a small molecule or small interfering RNA targeting NAT10, we examined the effect of NAT10 inhibition on melanogenesis and melanoma growth in human and mouse melanoma cells. Genetic silencing or chemical inhibition of NAT10 resulted in diminished melanin synthesis through the suppression of melanogenesis-stimulating genes such as those encoding dopachrome tautomerase (DCT) and tyrosinase in B16F10 melanoma cells. In addition, NAT10 inhibition significantly increased cell cycle arrest in S-phase, thereby suppressing the growth and proliferation of malignant melanoma cells in vitro and in vivo. These results demonstrate the potential role of NAT10 in melanogenesis and melanoma growth through the regulation of microphthalmia-associated transcription factor (MITF) expression and provide a promising strategy for the treatment of various skin diseases (melanoma) and pigmentation disorders (chloasma and freckles).

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Autoacetylation of NAT10 is critical for its function in rRNA transcription activation

Cited by 46 publications

References 38 publications

Deacetylation of NAT10 by Sirt1 promotes the transition from rRNA biogenesis to autophagy upon energy stress

Deacetylation of NAT10 by Sirt1 promotes the transition from rRNA biogenesis to autophagy upon energy stress

Arginine-GlcNAcylation of death domain and NleB/SseK proteins is crucial for bacteria pathogenesis by regulating host cell death

Inhibition of NAT10 Suppresses Melanogenesis and Melanoma Growth by Attenuating Microphthalmia-Associated Transcription Factor (MITF) Expression

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