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K235 acetylation couples with PSPC1 to regulate the m⁶A demethylation activity of ALKBH5 and tumorigenesis.

ABSTRACT: N6-methyladenosine (m⁶A) modification plays important roles in bioprocesses and diseases. AlkB homolog 5 (ALKBH5) is one of two m⁶A demethylases. Here, we reveal that ALKBH5 is acetylated at lysine 235 (K235) by lysine acetyltransferase 8 and deacetylated by histone deacetylase 7. K235 acetylation strengthens the m⁶A demethylation activity of ALKBH5 by increasing its recognition of m⁶A on mRNA. RNA-binding protein paraspeckle component 1 (PSCP1) is a regulatory subunit of ALKBH5 and preferentially interacts with K235-acetylated ALKBH5 to recruit and facilitate the recognition of m⁶A mRNA by ALKBH5, thereby promoting m⁶A erasure. Mitogenic signals promote ALKBH5 K235 acetylation. K235 acetylation of ALKBH5 is upregulated in cancers and promotes tumorigenesis. Thus, our findings reveal that the m⁶A demethylation activity of ALKBH5 is orchestrated by its K235 acetylation and regulatory subunit PSPC1 and that K235 acetylation is necessary for the m⁶A demethylase activity and oncogenic roles of ALKBH5.

SUBMITTER: Zhang XL

PROVIDER: S-EPMC10300122 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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K235 acetylation couples with PSPC1 to regulate the m6A demethylation activity of ALKBH5 and tumorigenesis.

Zhang Xiao-Lan XL Chen Xin-Hui XH Xu Binwu B Chen Min M Zhu Song S Meng Nan N Wang Ji-Zhong JZ Zhu Huifang H Chen De Liu Jin-Bao JB Yan Guang-Rong GR

Nature communications 20230627 1

N6-methyladenosine (m6A) modification plays important roles in bioprocesses and diseases. AlkB homolog 5 (ALKBH5) is one of two m6A demethylases. Here, we reveal that ALKBH5 is acetylated at lysine 235 (K235) by lysine acetyltransferase 8 and deacetylated by histone deacetylase 7. K235 acetylation strengthens the m6A demethylation activity of ALKBH5 by increasing its recognition of m6A on mRNA. RNA-binding protein paraspeckle component 1 (PSCP1) is a r ...[more]

PMID: 37369679

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Project description:BackgroundElevated extracellular matrix (ECM) accumulation is a major contributing factor to the pathogenesis of fibrotic diseases. Recent studies have indicated that N6-methyladenosine (m6A) RNA modification plays a pivotal role in modulating RNA stability and contribute to the initiation of various pathological conditions. Howbeit, the precise mechanism by which m6A influences ECM deposition remains unclear.MethodsIn this study, we used hypertrophic scars (HTSs) as a paradigm to investigate ECM-related diseases. We focused on the role of ALKBH5-mediated m6A demethylation within the pathological progression of HTSs and examined its correlation with clinical stages. The effects of ALKBH5 ablation on ECM components were studied both in vivo and in vitro. Downstream targets of ALKBH5, along with their underlying mechanisms, were identified using integrated high-throughput analysis, RNA-binding protein immunoprecipitation and RNA pull-down assays. Furthermore, the therapeutic potential of exogenous ALKBH5 overexpression was evaluated in fibrotic scar models.ResultsALKBH5 was decreased in fibroblasts derived from HTS lesions and was negatively correlated with their clinical stages. Importantly, ablation of ALKBH5 promoted the expression of COL3A1, COL1A1, and ELN, leading to pathological deposition and reconstruction of the ECM both in vivo and in vitro. From a therapeutic perspective, the exogenous overexpression of ALKBH5 significantly inhibited abnormal collagen deposition in fibrotic scar models. As determined by integrated high-throughput analysis, key ECM components including COL3A1, COL1A1, and ELN are direct downstream targets of ALKBH5. By means of its mechanism, ALKBH5 inhibits the expression of COL3A1, COL1A1, and ELN by removing m6A from mRNAs, thereby decreasing their stability in a YTHDF1-dependent manner.ConclusionsOur study identified ALKBH5 as an endogenous suppressor of pathological ECM deposition, contributing to the development of a reprogrammed m6A-targeted therapy for HTSs.

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K235 acetylation couples with PSPC1 to regulate the m⁶A demethylation activity of ALKBH5 and tumorigenesis.

Publications

K235 acetylation couples with PSPC1 to regulate the m<sup>6</sup>A demethylation activity of ALKBH5 and tumorigenesis.

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