The Post-Translational Role of UFMylation in Physiology and Disease

Wang, Xingde; Xu, Xingzhi; Wang, Zhifeng

doi:10.3390/cells12212543

Cited by 8 publications

(6 citation statements)

References 120 publications

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“…Although UFMylation was discovered about two decades ago, the majority of its substrates have only been identi ed in recent years (10,35). Research into these substrates has revealed a broad spectrum of functions associated with this modi cation.…”

Section: Discussionmentioning

confidence: 99%

Eg5 UFMylation promotes spindle organization during mitosis

Duan,

Li,

Huang

et al. 2024

Preprint

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UFMylation is a highly conserved ubiquitin-like post-translational modification that catalyzes the covalent linkage of UFM1 to its target proteins. This modification plays critical roles in the maintenance of endoplasmic reticulum (ER) proteostasis, DNA damage response, autophagy, and transcriptional regulation. Mutations in UFM1, as well as in its specific E1 enzyme UBA5 and E2 enzyme UFC1, have been genetically linked to microcephaly. Our previous research unveiled the important role of UFMylation in regulating mitosis. However, the underlying mechanisms have remained unclear due to the limited identification of substrates. In this study, we identified Eg5, a motor protein crucial for mitotic spindle assembly and maintenance, as a novel substrate for UFMylation and identified Lys564 as the crucial UFMylation site. UFMylation did not alter its transcriptional level, phosphorylation level, or protein stability, but affected the mono-ubiquitination of Eg5. During mitosis, Eg5 and UFM1 co-localize at the centrosome and spindle apparatus, and defective UFMylation leads to diminished spindle localization of Eg5. Notably, the UFMylation-defective mutant of Eg5 (K564R) displayed shortened or asymmetrical spindles, and suppressed cell proliferation in HeLa cells. Overall, Eg5 UFMylation is essential for proper spindle organization, mitotic progression and cell proliferation.

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Section: Discussionmentioning

confidence: 99%

Eg5 UFMylation promotes spindle organization during mitosis

Duan,

Li,

Huang

et al. 2024

Preprint

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“…It is possible that there is a general increase of UFM1 attached as monomer or in chains on one or several physiological substrates. Most knowledge about UFM1 substrates is derived from studies in cancer cell lines[ 15 , 27 , 55 , 56 ]. Alternatively, in AD UFM1 could accumulate on a substrate that is normally not modified by UFM1 and further studies are needed to investigate targets of physiological and pathological UFMylation in the brain.…”

Section: Discussionmentioning

confidence: 99%

“…Very recently, a group identified UFMylation as novel key modifier of seeding-induced Tau propagation[ 26 ]. In addition, UFMylation is essential for brain development, as loss of function of any of its components causes severe neurodevelopmental disorders[ 15 , 27 – 31 ]. Therefore, reduced functions of UFMylation could well affect neuronal function and viability.…”

Section: Introductionmentioning

confidence: 99%

The UFMylation pathway is impaired in Alzheimer’s disease

Yan,

Heckman,

Craver

et al. 2024

Preprint

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Background: Alzheimer's disease (AD) is characterized by the presence of neurofibrillary tangles made of hyperphosphorylated tau and senile plaques composed of beta-amyloid. These pathognomonic deposits have been implicated in the pathogenesis, although the molecular mechanisms and consequences remain undetermined. UFM1 is an important, but understudied ubiquitin-like protein that is covalently attached to substrates. This UFMylation has recently been identified as major modifier of tau aggregation upon seeding in experimental models. However, potential alterations of the UFM1 pathway in human AD brain have not been investigated yet. Methods: Here we used frontal and temporal cortex samples from individuals with or without AD to measure the protein levels of the UFMylation pathway in human brain. We used multivariable regression analyses followed by Bonferroni correction for multiple testing to analyze associations of the UFMylation pathway with neuropathological characteristics, primary biochemical measurements of tau and additional biochemical markers from the same cases. We further studied associations of the UFMylation cascade with cellular stress pathways using Spearman correlations with bulk RNAseq expression data and functionally validated these interactions using gene-edited neurons that were generated by CRISPR-Cas9. Results: Compared to controls, human AD brain had increased protein levels of UFM1. Our data further indicates that this increase mainly reflects conjugated UFM1 indicating hyperUFMylation in AD. UFMylation was strongly correlated with pathological tau in both AD-affected brain regions. In addition, we found that the levels of conjugated UFM1 were negatively correlated with soluble levels of the deUFMylation enzyme UFSP2. Functional analysis of UFM1 and/or UFSP2 knockout neurons revealed that the DNA damage response as well as the unfolded protein response are perturbed by changes in neuronal UFM1 signaling. Conclusions: There are marked changes in the UFMylation pathway in human AD brain. These changes are significantly associated with pathological tau, supporting the idea that the UFMylation cascade might indeed act as a modifier of tau pathology in human brain. Our study further nominates UFSP2 as an attractive target to reduce the hyperUFMylation observed in AD brain but also underscores the critical need to identify risks and benefits of manipulating the UFMylation pathway as potential therapeutic avenue for AD.

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“…UFMylation has predominantly been linked to roles in endoplasmic reticulum (ER) homeostasis, fatty acid metabolism, autophagy, neurodevelopment, and liver development [ 263 , 264 , 267 , 268 ]. A major substrate for UFMylation is the 60S ribosomal subunit RPL26, which occurs on stalled ribosomes at the ER.…”

Section: Ulps In Genome Stabilitymentioning

confidence: 99%

DoUBLing up: ubiquitin and ubiquitin-like proteases in genome stability

Foster,

Wang,

Schmidt

2024

Biochemical Journal

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Maintaining stability of the genome requires dedicated DNA repair and signalling processes that are essential for the faithful duplication and propagation of chromosomes. These DNA damage response (DDR) mechanisms counteract the potentially mutagenic impact of daily genotoxic stresses from both exogenous and endogenous sources. Inherent to these DNA repair pathways is the activity of protein factors that instigate repair processes in response to DNA lesions. The regulation, coordination, and orchestration of these DDR factors is carried out, in a large part, by post-translational modifications, such as phosphorylation, ubiquitylation, and modification with ubiquitin-like proteins (UBLs). The importance of ubiquitylation and UBLylation with SUMO in DNA repair is well established, with the modified targets and downstream signalling consequences relatively well characterised. However, the role of dedicated erasers for ubiquitin and UBLs, known as deubiquitylases (DUBs) and ubiquitin-like proteases (ULPs) respectively, in genome stability is less well established, particularly for emerging UBLs such as ISG15 and UFM1. In this review, we provide an overview of the known regulatory roles and mechanisms of DUBs and ULPs involved in genome stability pathways. Expanding our understanding of the molecular agents and mechanisms underlying the removal of ubiquitin and UBL modifications will be fundamental for progressing our knowledge of the DDR and likely provide new therapeutic avenues for relevant human diseases, such as cancer.

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The Post-Translational Role of UFMylation in Physiology and Disease

Cited by 8 publications

References 120 publications

Eg5 UFMylation promotes spindle organization during mitosis

Eg5 UFMylation promotes spindle organization during mitosis

The UFMylation pathway is impaired in Alzheimer’s disease

DoUBLing up: ubiquitin and ubiquitin-like proteases in genome stability

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