Dynamic crotonylation of EB1 by TIP60 ensures accurate spindle positioning in mitosis

Song, Xiaoyu; Yang, Fengrui; Liu, Xu; Xia, Peng; Wu, Yin; Wang, Zhikai; Wang, Yong; Yuan, Xiao; Dou, Zhen; Jiang, Kai; Ma, Mingming; Hu, Bing; Zhang, Rui; Xu, Chao; Zhang, Zhiyong; Ruan, Ke‐He; Tian, Ruijun; Li, Lin; Liu, Tao; Hill, Donald L.; Zang, Jianye; Liu, Xing; Li, Jinsong; Cheng, Jinke; Yao, Xuebiao

doi:10.1038/s41589-021-00875-7

Cited by 48 publications

(42 citation statements)

References 52 publications

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“…As a widely known acetyltransferase, Tip60 regulates other acylations as well. For example, in a recent study, Tip60 accurately controlled spindle positioning during mitosis by mediating crotonylation at Lys66 on EB1 [ 31 ]. Interestingly, the Lys66 site can also be acetylated by Tip60 in vitro, which suggests that Tip60 regulates its target substrates and corresponding biological processes in a complex way.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Proteomics Reveals the Role of Lysine 2-Hydroxyisobutyrylation Pathway Mediated by Tip60

Wang

Jiang

Peng

et al. 2022

Oxidative Medicine and Cellular Longevity

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Lysine 2-hydroxyisobutyrylation (Khib) is a new type of posttranslational modifications (PTMs) extensively reported on eukaryotic cell histones. It is evolutionarily conserved and participates in diverse important biological processes, such as transcription and cell metabolism. Recently, it has been demonstrated that Khib can be regulated by p300 and Tip60. Although the specific Khib substrates mediated by p300 have been revealed, how Tip60 regulates diverse cellular processes through the Khib pathway and the different roles between Tip60 and p300 in regulating Khib remain largely unknown, which prevents us from understanding how this modification executes its biological functions. In this study, we report the first Khib proteome mediated by Tip60. In total, 3502 unique Khib sites from 1050 proteins were identified. Among them, 536 Khib sites from 406 proteins were present only in Tip60 overexpressing cells and 13 Khib sites increased more than 2-fold in response to Tip60 overexpression, indicating that Tip60 significantly affected global Khib. Notably, only 5 of the 549 Tip60-targeted Khib sites overlapped with the 149 known Khib sites targeted by p300, indicating the different Khib substrate preferences of Tip60 and p300. In addition, the Khib substrates regulated by Tip60 are deeply involved in processes such as nucleic acid metabolism and translation, and some are associated with Parkinson’s and Prion diseases. In summary, our research reveals the Khib substrates targeted by Tip60, which elucidates the effect of Tip60 in regulating various cellular processes through the Khib pathway, and proposes novel views into the functional mechanism of Tip60.

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Section: Discussionmentioning

confidence: 99%

Quantitative Proteomics Reveals the Role of Lysine 2-Hydroxyisobutyrylation Pathway Mediated by Tip60

Wang

Jiang

Peng

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…A recent study showed that dynamic crotonylation of EB1 regulated accurate microtubule dynamics in mitosis [10], thus ensuring that vertebrate cells divide in the correct orientation. EB1 has been found to compete with SEPT2 for binding to guanosine' 5'-O-[γ-thio] triphosphate (GTPγS)-stabilized microtubules [26].…”

Section: Discussionmentioning

confidence: 99%

“…In 2017, Kcr was found in numerous nonhistone proteins and is thought to play roles in multiple cellular functions. [8,9] Recent studies have shown that crotonylation of nonhistone proteins ensures accurate spindle positioning in mitosis [10] and is related to aging [11] and colorectal cancer progression [12]. However, our understanding of Kcr is far from su cient.…”

Section: Introductionmentioning

confidence: 99%

SEPT2 Protein Crotonylation Promotes Metastasis and Recurrence Through AKT Pathway in Hepatocellular Carcinoma and is Associated with Poor Survival

Zhang

Liu

Zhang

et al. 2022

Preprint

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Background Hepatocellular carcinoma (HCC) metastasis and recurrence lead to therapy failure. Posttranslational modification (PTM) mechanisms in HCC, especially those of recently discovered PTMs, such as lysine crotonylation (Kcr), are still poorly understood. Methods Kcr protein levels in HCC cell lines of MHCC-97H (highly invasive) cells and MHCC-97L (minimally invasive) were detected through stable isotope labeling by amino acids in cell culture (SILAC) and liquid chromatography with tandem mass spectrometry (LC–MS/MS). The differentially crotonylated proteins in these two cell lines were identified through bioinformatics analysis. Protein Kcr was confirmed by immunoprecipitation (IP) and western blotting (WB). The function of Septin2 (SEPT2) crotonylated at K74 (SEPT2-K74cr) in metastasis was examined in vivo and in vitro. The clinical significance of SEPT2-K74cr in HCC patients was determined by immunohistochemistry (IHC) assay. Results The crotonylation rate was higher in highly invasive cells, and higher crotonylation level in HCC cells facilitated cell migration and invasion. The crotonylated protein SEPT2 was significantly hypercrotonylated in highly invasive cells, and the de-crotonylated mutation of K74 in SEPT2 impaired SEPT2 GTPase activity and inhibited HCC metastasis in vitro and in vivo. Mechanistically, SIRT2 decrotonylated SEPT2, and P85α was found to be the downstream effector of SEPT2. SEPT2-K74R facilitated P85α degradation, suppressing PI3K pathway and inhibiting the epithelial–mesenchymal transition. SEPT2-K74cr was correlated with poor prognosis and recurrence in HCC patients. Conclusions We revealed the role of nonhistone protein crotonylation in regulating HCC metastasis and invasion. Crotonylation facilitated cell invasion through the crotonylated SEPT2-K74 (cr)-P85α-AKT pathway. High SEPT2-K74 crotonylation predicted poor prognosis and a high recurrence rate in HCC patients.

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“…Notably, Kcr can be modulated enzymatically by P300/CBP with sodium crotonate serving as the substrate [ 70 ] and metabolically on the basis of the concentration of the intermediate metabolite crotonyl-CoA, which increases during mitochondrial or peroxisomal fatty acid oxidation, as well as lysine and tryptophan metabolism [ 28 ]. Later, PCAF, MOF, KAT6A, HBO1 and Tip60 were identified as catalysts of Kcr [ 33 , 71 – 74 ], and the opposite reaction is mediated by the histone deacetylases HDAC3 [ 75 ] and SIRT1–3 [ 76 ], with SIRT3 being the major decrotonylase in living cells [ 77 ]. Notably, a recent study asserted that class I HDACs are the principal histone decrotonylases [ 78 ].…”

Section: Introductionmentioning

confidence: 99%

“…According to previous findings that histone Kcr participates in the DNA damage response [ 31 ] and CDYL promotes homology-directed repair (HDR) [ 87 , 88 ], scientists further revealed a key role of CDYL-regulated RPA1 crotonylation in the HDR process [ 32 ]. In addition, Kcr of EB1, a core and scaffold microtubule plus-end tracking protein, ensures accurate spindle positioning in mitosis [ 33 ]. Kcr-AF9 YEATS interactions are promoted by crotonate pretreatment, positively regulating gene expression in the inflammatory response [ 80 ].…”

Section: Introductionmentioning

confidence: 99%

Oncometabolites drive tumorigenesis by enhancing protein acylation: from chromosomal remodelling to nonhistone modification

et al. 2022

J Exp Clin Cancer Res

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Metabolites are intermediate products of cellular metabolism catalysed by various enzymes. Metabolic remodelling, as a biochemical fingerprint of cancer cells, causes abnormal metabolite accumulation. These metabolites mainly generate energy or serve as signal transduction mediators via noncovalent interactions. After the development of highly sensitive mass spectrometry technology, various metabolites were shown to covalently modify proteins via forms of lysine acylation, including lysine acetylation, crotonylation, lactylation, succinylation, propionylation, butyrylation, malonylation, glutarylation, 2-hydroxyisobutyrylation and β-hydroxybutyrylation. These modifications can regulate gene expression and intracellular signalling pathways, highlighting the extensive roles of metabolites. Lysine acetylation is not discussed in detail in this review since it has been broadly investigated. We focus on the nine aforementioned novel lysine acylations beyond acetylation, which can be classified into two categories: histone acylations and nonhistone acylations. We summarize the characteristics and common functions of these acylation types and, most importantly, provide a glimpse into their fine-tuned control of tumorigenesis and potential value in tumour diagnosis, monitoring and therapy.

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Dynamic crotonylation of EB1 by TIP60 ensures accurate spindle positioning in mitosis

Cited by 48 publications

References 52 publications

Quantitative Proteomics Reveals the Role of Lysine 2-Hydroxyisobutyrylation Pathway Mediated by Tip60

Quantitative Proteomics Reveals the Role of Lysine 2-Hydroxyisobutyrylation Pathway Mediated by Tip60

SEPT2 Protein Crotonylation Promotes Metastasis and Recurrence Through AKT Pathway in Hepatocellular Carcinoma and is Associated with Poor Survival

Oncometabolites drive tumorigenesis by enhancing protein acylation: from chromosomal remodelling to nonhistone modification

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