SCF-FBXO24 regulates cell proliferation by mediating ubiquitination and degradation of PRMT6

Chen, Wei; Gao, Derong; Xie, Long; Wang, Anling; Guo, Chaowan; Sun, Yongtao; Nie, Yanfeng; An, Hongyu; Xiong, Sheng

doi:10.1016/j.bbrc.2020.06.007

Cited by 14 publications

(9 citation statements)

References 21 publications

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“…Western blot analyses revealed that the protein level of MIWI was remarkably increased in the Fbxo24 KO testes compared with WT ( Figure 4E ) . However, the level of other proteins of CB, and PRMT6 (reported to be the substrate of FBXO24)(9) appeared to be unchanged in Fbxo24 KO testes compared with WT testis ( Figure 4E ) . These results suggest that FBXO24 is essential for maintaining the normal architecture of mitochondria and CB in the round spermatids.…”

Section: Resultsmentioning

confidence: 97%

“…In addition, FBXO24 has been reported to recognize deacetylated nucleoside diphosphate kinase A (NDPK-A) to enhance its degradation in HeLa cells (8). In H1299 cells, FBXO24 could promote cell proliferation by mediating ubiquitination and degradation of protein arginine methyltransferase 6 (PRMT6) (9). However, the molecular and biological functions of FBXO24 in mammals remain unclear, especially its role in male fertility and spermatogenesis.…”

Section: Introductionmentioning

confidence: 99%

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FBXO24 modulates mRNA alternative splicing and MIWI degradation and is required for normal sperm formation and piRNA production

Li,

Liu,

Zhang

et al. 2023

Preprint

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Spermiogenesis is a critical, post-meiotic phase of male gametogenesis, in which the proper gene expression is essential for sperm maturation. However, the underlying molecular mechanism that controls mRNA expression in the round spermatids remains elusive. Here, we identify that FBXO24, an orphan F-box protein, is highly expressed in the testis of humans and mice and interacts with the splicing factors (SRSF2, SRSF3, and SRSF9) to modulate the gene alternative splicing in the round spermatids. Genetic mutation of FBXO24 in mice causes many abnormal splicing events in round spermatids, thus affecting a large number of critical genes related to sperm formation that were dysregulated. Further molecular and phenotypical analyses revealed that FBXO24 deficiency results in aberrant histone retention, incomplete axonemes, oversized chromatoid body (CB), and abnormal mitochondrial coiling along sperm flagella, ultimately leading to male sterility. In addition, we discovered that FBXO24 interacts with MIWI and SCF subunits and mediates the degradation of MIWI via K48-linked polyubiquitination. Furthermore, we show that FBXO24 depletion could lead to aberrant piRNA production in testes, which suggests FBXO24 is required for normal piRNA biogenesis. Collectively, these data demonstrate that FBXO24 is essential for sperm formation and piRNA production by regulating mRNA alternative splicing and MIWI degradation during spermiogenesis.

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Section: Resultsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

FBXO24 modulates mRNA alternative splicing and MIWI degradation and is required for normal sperm formation and piRNA production

Li,

Liu,

Zhang

et al. 2023

Preprint

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“…Alternatively, Prmt6 transcript stability could be regulated by RNA-methylation as was recently described for Prmt6 28 . There is also evidence for regulation of Prmt6 by proteasomal degradation 29 , 30 . In our hands, treatment of proteasome inhibitor MG132 did not lead to an increased Prmt6 protein level in ST2 cells (Supplemental Figure S3 ).…”

Section: Discussionmentioning

confidence: 99%

Prmt6 represses the pro-adipogenic Ppar-gamma–C/ebp-alpha transcription factor loop

Gerstner,

Heller,

Fechner

et al. 2024

Sci Rep

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The feed-forward loop between the transcription factors Ppar-gamma and C/ebp-alpha is critical for lineage commitment during adipocytic differentiation. Ppar-gamma interacts with epigenetic cofactors to activate C/ebp-alpha and the downstream adipocytic gene expression program. Therefore, knowledge of the epigenetic cofactors associated with Ppar-gamma, is central to understanding adipocyte differentiation in normal differentiation and disease. We found that Prmt6 is present with Ppar-gamma on the Ppar-gamma and C/ebp-alpha promoter. It contributes to the repression of C/ebp-alpha expression, in part through its ability to induce H3R2me2a. During adipocyte differentiation, Prmt6 expression is reduced and the methyltransferase leaves the promoters. As a result, the expression of Ppar-gamma and C/ebp-alpha is upregulated and the adipocytic gene expression program is established. Inhibition of Prmt6 by a small molecule enhances adipogenesis, opening up the possibility of epigenetic manipulation of differentiation. Our data provide detailed information on the molecular mechanism controlling the Ppar-gamma–C/ebp-alpha feed-forward loop. Thus, they advance our understanding of adipogenesis in normal and aberrant adipogenesis.

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“…PRMT1 is ubiquitinated by E4B (Bhuripanyo et al 2018 ), CARM1 by Skp, Cullin, F-box-containing complex (SCF) (Shin et al 2016 ), and PRMT5 by carboxy-terminus of Hsc70-interacting protein (CHIP) ligase (Zhang et al 2016 ). Recently, an orphan F-box protein, FBXO24, has been shown to modify PRMT6 by ubiquitination at K369 (Chen et al 2020 ). Although questions remain about the specific ubiquitination sites on other PRMTs, it is generally accepted that modification by (poly)ubiquitination leads to proteasomal degradation of PRMTs (Hartley and Lu 2020 ).…”

Section: Regulation Of Arginine Methylationmentioning

confidence: 99%

Arginine methylation: the promise of a ‘silver bullet’ for brain tumours?

et al. 2021

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Despite intense research efforts, our pharmaceutical repertoire against high-grade brain tumours has not been able to increase patient survival for a decade and life expectancy remains at less than 16 months after diagnosis, on average. Inhibitors of protein arginine methyltransferases (PRMTs) have been developed and investigated over the past 15 years and have now entered oncology clinical trials, including for brain tumours. This review collates recent advances in the understanding of the role of PRMTs and arginine methylation in brain tumours. We provide an up-to-date literature review on the mechanisms for PRMT regulation. These include endogenous modulators such as alternative splicing, miRNA, post-translational modifications and PRMT–protein interactions, and synthetic inhibitors. We discuss the relevance of PRMTs in brain tumours with a particular focus on PRMT1, -2, -5 and -8. Finally, we include a future perspective where we discuss possible routes for further research on arginine methylation and on the use of PRMT inhibitors in the context of brain tumours.

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SCF-FBXO24 regulates cell proliferation by mediating ubiquitination and degradation of PRMT6

Cited by 14 publications

References 21 publications

FBXO24 modulates mRNA alternative splicing and MIWI degradation and is required for normal sperm formation and piRNA production

FBXO24 modulates mRNA alternative splicing and MIWI degradation and is required for normal sperm formation and piRNA production

Prmt6 represses the pro-adipogenic Ppar-gamma–C/ebp-alpha transcription factor loop

Arginine methylation: the promise of a ‘silver bullet’ for brain tumours?

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