Phase separation of BuGZ regulates gut regeneration and aging through interaction with m6A regulators

Zhang, Qiaoqiao; Deng, Kai; Liu, Mengyou; Yang, Shengye; Xu, Wei; Feng, Tong; Jie, Minwen; Liu, Zhiming; Sheng, Xiao; Chen, Haiyang; Jiang, Hao

doi:10.1038/s41467-023-42474-1

Cited by 7 publications

(5 citation statements)

References 67 publications

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“…Another open question concerns the maintenance of oxidation processes in the reductive cytosol. In recent studies, LLPS has gained attention as a new principle of subcellular organization 21,47,48 . For gephyrin it was recently demonstrated that it forms liquid droplets in the presence of a multimeric receptor model 22 .…”

Section: Discussionmentioning

confidence: 99%

Redox-dependent synaptic clustering of gephyrin

Gehling,

Liebsch,

Jacobs

et al. 2024

Preprint

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Reactive oxygen species (ROS) play a central role in enhancing inhibitory signal transmission, thus extending their role beyond oxidative stress in disease and aging. However, the underlying molecular mechanisms mediating these functions have remained elusive. At inhibitory synapses, the scaffolding protein gephyrin clusters glycine and GABA type A receptors. Since gephyrin harbors multiple surface-exposed cysteines, we investigated the regulatory influence of ROS on gephyrin. We show that H2O2-induced oxidation of gephyrin cysteines triggered reversible, synaptic multimerization through disulfide bridge formation, which provided more receptor binding sites, lead to proteolytic protection and enhanced liquid-liquid phase separation. We identified mitochondria-derived ROS as a physiological source and observed oxidized gephyrin multimers in vivo, indicating that gephyrin can be regulated by the redox environment. Collectively, our findings suggest that cysteines in gephyrin modulate synaptic localization and clustering as regulatory redox-switches thereby establishing a link between neuronal and mitochondrial activity.

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Section: Discussionmentioning

confidence: 99%

Redox-dependent synaptic clustering of gephyrin

Gehling,

Liebsch,

Jacobs

et al. 2024

Preprint

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“…Despite IDPs being often poorly conserved ( 42 , 43 ), SUF4 shares substantial homology with the animal protein BuGZ. In these organisms, BuGZ plays essential roles in both mitotic and transcriptional regulation by interacting with various cellular machineries, including the spindle assembly checkpoint protein (SAC) Bub3, the spliceosome, and epigenetic factors ( 13 , 14 , 44 ). While SUF4’s primary function in plants revolves around regulating flowering time, recent research has unveiled its potential involvement in analogous mitotic and transcriptional regulatory processes ( 45–47 ).These newfound roles raise a series of questions, including whether SUF4’s phase separation has evolved distinct functionality specific to plant flowering or if it serves as a universal mechanism within eukaryotic systems.…”

Section: Discussionmentioning

confidence: 99%

“…SUF4 is an ortholog of the animal protein BuGZ (Supplemental Figure 3), an IDP initially found to undergo temperature-dependent phase separation in vitro and regulate spindle assembly in vivo (13)(14)(15). Therefore, to assess the potential for SUF4 to undergo phase separation independently of any plant cell factors, we expressed and purified 6xHis-mVenus-SUF4 (isoform 1, WT) from SF9 insect cells.…”

Section: Suf4 Phase Separates In Vitromentioning

confidence: 99%

“…SUF4 makes an excellent candidate for untangling the relationship between protein phase separation behavior and plant temperature sensing because it has a well-defined genetic and molecular role in temperature-dependent flowering by acting to transcriptionally regulate FLC under warm temperature conditions. Furthermore, it exhibits structural and biochemical similarities to BuGZ, a mammalian IDP that is prolinerich and undergoes temperature-dependent phase separation under in vitro conditions (13)(14)(15). Using confocal microscopy, genetics and biochemistry, we have discovered that SUF4 is a temperature-sensitive protein that phase separates in vitro to form proteinaceous droplets and in planta to promote the formation of nuclear condensates.…”

Section: Introductionmentioning

confidence: 99%

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Manipulating condensation of thermo-sensitive SUF4 protein tunes flowering time in Arabidopsis thaliana

Meyer,

Hotta,

Malkovskiy

et al. 2023

Preprint

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Intrinsically disordered proteins (IDP) lack stable tertiary structures, which allows them to change conformation and function under different physicochemical conditions. This may be highly advantageous for plants, which often use changes in their environment to trigger developmental events. For instance, some plants use exposure to winter temperatures as a cue to initiate flowering the following spring. Many of the genes involved in temperature-dependent flowering have been extensively studied inArabidopsis, yet how plants perceive temperature changes is poorly understood. Here, we explore the role of temperature-sensitive phase separation of the IDP and flowering-time regulator, SUPPRESSOR OF FRIGIDA 4 (SUF4), in modulating flowering time. SUF4 has a well-defined role in regulating temperature-dependent flowering time by activating the master floral suppressorFLOWERING LOCUS C (FLC). We show that in plant nuclei, SUF4 is a temperature-sensitive protein that assembles into biomolecular condensates in warm temperatures (20°C). When temperatures cool (4°C), SUF4 nuclear condensates disassemble, causing SUF4 to disperse within the nucleoplasm. Additionally, we demonstrate that the number of SUF4 condensates quantitatively correlates with flowering time. Progressive alterations to the amino acid composition of SUF4’s disordered region cause likewise progressive changes in temperature-dependent condensation bothin vitroandin vivo,FLCtranscription, and the onset of flowering. We also observe that SUF4 condensates coincide with the accumulation of other key flowering-time proteins (FRIGIDA and ELF7). These findings indicate that condensation of SUF4 likely plays a pivotal role in promoting flowering, possibly by concentrating and stabilizing the regulatory factors needed for the transcriptional activation ofFLCthrough temperature-dependent phase separation. This research suggests that in plants, IDPs can sense environmental cues and regulate critical developmental processes.

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“…The overexpression of ZNF207 has been significantly associated with poor clinical outcomes in liver malignancies. Previous studies revealed the involvement of ZNF207 in the modulation of stem cell self-renewal and pluripotency, as well as its influence on chromosome arrangement. ,, Inhibiting ZNF207 affects the BUB3 mitotic checkpoint protein (BUB3) and BUB1 mitotic checkpoint serine/threonine kinase (BUB1) kinetochore localization, causing defects in spindle formation in GSCs and other transformed cells but not in human neural stem cells or nontransformed ones. Moreover, it has been observed that in p53-deficient CSCs, targeting ZNF207 might enhance the sensitivity of tumor cells to cisplatin by inhibiting spindle assembly checkpoints .…”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel N-(Anthracen-9-ylmethyl) Benzamide Derivatives as ZNF207 Inhibitors Promising in Treating Glioma

Zhang,

Ding,

Gao

et al. 2024

J. Med. Chem.

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Targeting tumor stemness is an innovative approach to cancer treatment. Zinc Finger Protein 207 (ZNF207) is a promising target for weakening the stemness of glioma cells. Here, a series of novel N-(anthracen-9-ylmethyl) benzamide derivatives against ZNF207 were rationally designed and synthesized. The inhibitory activity was evaluated, and their structure−activity relationships were summarized. Among them, C16 exhibited the most potent inhibitory activity, as evidenced by its IC 50 values ranging from 0.5−2.5 μM for inhibiting sphere formation and 0.5− 15 μM for cytotoxicity. Furthermore, we found that C16 could hinder tumorigenesis and migration and promote apoptosis in vitro. These effects were attributed to the downregulation of stem-related genes. The in vivo evaluation demonstrated that C16 exhibited efficient permeability across the blood−brain barrier and potent efficacy in both subcutaneous and orthotopic glioma tumor models. Hence, C16 may serve as a potential lead compound targeting ZNF207 and has promising therapeutic potential for glioma.

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Phase separation of BuGZ regulates gut regeneration and aging through interaction with m6A regulators

Cited by 7 publications

References 67 publications

Redox-dependent synaptic clustering of gephyrin

Redox-dependent synaptic clustering of gephyrin

Manipulating condensation of thermo-sensitive SUF4 protein tunes flowering time in Arabidopsis thaliana

Discovery of Novel N-(Anthracen-9-ylmethyl) Benzamide Derivatives as ZNF207 Inhibitors Promising in Treating Glioma

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