The deubiquitylating enzyme Ubp12 regulates Rad23-dependent proteasomal degradation

Gödderz, Daniela; Giovannucci, Tatiana A.; Laláková, Jana; Menéndez‐Benito, Victoria; Dantuma, Nico P.

doi:10.1242/jcs.202622

Cited by 16 publications

(13 citation statements)

References 47 publications

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“…In contrast to numerous proteins that are destabilized in absence of DUBs, deletion of UBP12 stabilizes Fzo1 ( Figure 6—figure supplement 1 ) and Ubp2 ( Figure 5B ). Consistently, the two other known substrates of Ubp12 – Rad23 ( Gödderz et al, 2017 ) and Gpa1 ( Wang et al, 2005 ) are also not destabilized in Δ ubp12 cells. To characterize the deubiquitylation reaction of Ubp12 in more detail, we analyzed the ubiquitin linkages on Fzo1 and Ubp2 accumulating in Δ ubp12 cells.…”

Section: Resultssupporting

confidence: 58%

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Cdc48 regulates a deubiquitylase cascade critical for mitochondrial fusion

Simões

Schuster

Brave

et al. 2018

eLife

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Cdc48/p97, a ubiquitin-selective chaperone, orchestrates the function of E3 ligases and deubiquitylases (DUBs). Here, we identify a new function of Cdc48 in ubiquitin-dependent regulation of mitochondrial dynamics. The DUBs Ubp12 and Ubp2 exert opposing effects on mitochondrial fusion and cleave different ubiquitin chains on the mitofusin Fzo1. We demonstrate that Cdc48 integrates the activities of these two DUBs, which are themselves ubiquitylated. First, Cdc48 promotes proteolysis of Ubp12, stabilizing pro-fusion ubiquitylation on Fzo1. Second, loss of Ubp12 stabilizes Ubp2 and thereby facilitates removal of ubiquitin chains on Fzo1 inhibiting fusion. Thus, Cdc48 synergistically regulates the ubiquitylation status of Fzo1, allowing to control the balance between activation or repression of mitochondrial fusion. In conclusion, we unravel a new cascade of ubiquitylation events, comprising Cdc48 and two DUBs, fine-tuning the fusogenic activity of Fzo1.

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Section: Resultssupporting

confidence: 58%

“…In contrast, the turnover of both Fzo1 and Ubp2 is decreased in Δ ubp12 cells. Moreover, Ubp12 does not stabilize Rad23 ( Gödderz et al, 2017 ) and Gpa1 ( Wang et al, 2005 ), i.e. its two other known substrates.…”

Section: Discussionmentioning

confidence: 97%

Cdc48 regulates a deubiquitylase cascade critical for mitochondrial fusion

Simões

Schuster

Brave

et al. 2018

eLife

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“…Thus, photorepair of UV‐induced DNA lesions and photoreactivation of UV‐impaired cells form a fundamental mechanism of fungal photoprotection. The NER process has been studied mainly in model yeast 47, 127 but rarely explored in filamentous fungi, and depends on the activities of helicases, endonucleases, polymerases, ligases and the interactions of multiple proteins involved in proteasome activity and poly‐ubiquitination in the dark 128–130 …”

Section: Photoprotection Of Fungal Cells From Uv Damagementioning

confidence: 99%

Molecular basis and regulatory mechanisms underlying fungal insecticides' resistance to solar ultraviolet irradiation

Tong

Feng

2021

Pest Management Science

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Resistance to solar ultraviolet (UV) irradiation is crucial for field‐persistent control efficacies of fungal formulations against arthropod pests, because their active ingredients are formulated conidia very sensitive to solar UV wavelengths. This review seeks to summarize advances in studies aiming to quantify, understand and improve conidial UV resistance. One focus of studies has been on the many sets of genes that have been revealed in the postgenomic era to contribute to or mediate UV resistance in the insect pathogens serving as main sources of fungal insecticides. Such genetic studies have unveiled the broad basis of UV‐resistant molecules including cytosolic solutes, cell wall components, various antioxidant enzymes, and numerous effectors and signaling proteins, that function in developmental, biosynthetic and stress‐responsive pathways. Another focus has been on the molecular basis and regulatory mechanisms underlying photorepair of UV‐induced DNA lesions and photoreactivation of UV‐impaired conidia. Studies have shed light upon a photoprotective mechanism depending on not only one or two photorepair‐required photolyases, but also two white collar proteins and other partners that play similar or more important roles in photorepair via interactions with photolyases. Research hotspots are suggested to explore a regulatory network of fungal photoprotection and to improve the development and application strategies of UV‐resistant fungal insecticides. © 2021 Society of Chemical Industry.

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“…In the yeast, RAD23 can escape degradation due to a lack of proteasome initiation region (22), and it plays a main role in the NER by direct participation in both the repair biochemistry and stabilization of RAD4, a protein that mediates impaired DNA binding and recognition (23)(24)(25). Aside from RAD4, RAD23 interacts with many proteins involved in the proteasome activity and ubiquitin chains, including other Rad and related partners, the CDC48-RAD23/DSK2 axis involved in K48-linked chain specificity of the proteasome (26), and the deubiquitylating enzyme UBP12 that regulates RAD23dependent proteasomal degradation (27). These intensive studies demonstrate a core role of the yeast RAD23 in multiple cellular processes and events.…”

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confidence: 99%

Photoprotective Role of Photolyase-Interacting RAD23 and Its Pleiotropic Effect on the Insect-Pathogenic Fungus Beauveria bassiana

Wang

Mou

Tong

et al. 2020

Appl Environ Microbiol

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RAD23 can repair yeast DNA lesions through nucleotide excision repair (NER), a mechanism that is dependent on proteasome activity and ubiquitin chains but different from photolyase-depending photorepair of UV-induced DNA damages. However, this accessory NER protein remains functionally unknown in filamentous fungi. In this study, orthologous RAD23 in Beauveria bassiana, an insect-pathogenic fungus that is a main source of fungal insecticides, was found to interact with the photolyase PHR2, enabling repair of DNA lesions by degradation of UVB-induced cytotoxic (6-4)-pyrimidine-pyrimidine photoproducts under visible light, and it hence plays an essential role in the photoreactivation of UVB-inactivated conidia but no role in reactivation of such conidia through NER in dark conditions. Fluorescence-labeled RAD23 was shown to normally localize in the cytoplasm, to migrate to vacuoles in the absence of carbon, nitrogen, or both, and to enter nuclei under various stresses, which include UVB, a harmful wavelength of sunlight. Deletion of the rad23 gene resulted in an 84% decrease in conidial UVB resistance, a 95% reduction in photoreactivation rate of UVB-inactivated conidia, and a drastic repression of phr2. A yeast two-hybrid assay revealed a positive RAD23-PHR2 interaction. Overexpression of phr2 in the Δrad23 mutant largely mitigated the severe defect of the Δrad23 mutant in photoreactivation. Also, the deletion mutant was severely compromised in radial growth, conidiation, conidial quality, virulence, multiple stress tolerance, and transcriptional expression of many phenotype-related genes. These findings unveil not only the pleiotropic effects of RAD23 in B. bassiana but also a novel RAD23-PHR2 interaction that is essential for the photoprotection of filamentous fungal cells from UVB damage. IMPORTANCE RAD23 is able to repair yeast DNA lesions through nucleotide excision in full darkness, a mechanism distinct from photolyase-dependent photorepair of UV-induced DNA damage but functionally unknown in filamentous fungi. Our study unveils that the RAD23 ortholog in a filamentous fungal insect pathogen varies in subcellular localization according to external cues, interacts with a photolyase required for photorepair of cytotoxic (6-4)-pyrimidine-pyrimidine photoproducts in UV-induced DNA lesions, and plays an essential role in conidial UVB resistance and reactivation of UVB-inactivated conidia under visible light rather than in the dark, as required for nucleotide excision repair. Loss-of-function mutations of RAD23 exert pleiotropic effects on radial growth, aerial conidiation, multiple stress responses, virulence, virulence-related cellular events, and phenotype-related gene expression. These findings highlight a novel mechanism underlying the photoreactivation of UVB-impaired fungal cells by RAD23 interacting with the photolyase, as well as its essentiality for filamentous fungal life.

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The deubiquitylating enzyme Ubp12 regulates Rad23-dependent proteasomal degradation

Cited by 16 publications

References 47 publications

Cdc48 regulates a deubiquitylase cascade critical for mitochondrial fusion

Cdc48 regulates a deubiquitylase cascade critical for mitochondrial fusion

Molecular basis and regulatory mechanisms underlying fungal insecticides' resistance to solar ultraviolet irradiation

Photoprotective Role of Photolyase-Interacting RAD23 and Its Pleiotropic Effect on the Insect-Pathogenic Fungus Beauveria bassiana

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