post translational modification
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2022 ◽  
Vol 27 (1) ◽  
Author(s):  
Hongjuan You ◽  
Qi Li ◽  
Delong Kong ◽  
Xiangye Liu ◽  
Fanyun Kong ◽  
...  

AbstractCanonical Wnt/β-catenin signaling is a complex cell-communication mechanism that has a central role in the progression of various cancers. The cellular factors that participate in the regulation of this signaling are still not fully elucidated. Lysine acetylation is a significant protein modification which facilitates reversible regulation of the target protein function dependent on the activity of lysine acetyltransferases (KATs) and the catalytic function of lysine deacetylases (KDACs). Protein lysine acetylation has been classified into histone acetylation and non-histone protein acetylation. Histone acetylation is a kind of epigenetic modification, and it can modulate the transcription of important biological molecules in Wnt/β-catenin signaling. Additionally, as a type of post-translational modification, non-histone acetylation directly alters the function of the core molecules in Wnt/β-catenin signaling. Conversely, this signaling can regulate the expression and function of target molecules based on histone or non-histone protein acetylation. To date, various inhibitors targeting KATs and KDACs have been discovered, and some of these inhibitors exert their anti-tumor activity via blocking Wnt/β-catenin signaling. Here, we discuss the available evidence in understanding the complicated interaction of protein lysine acetylation with Wnt/β-catenin signaling, and lysine acetylation as a new target for cancer therapy via controlling this signaling.


2022 ◽  
Author(s):  
Murat C Kalem ◽  
Harini Subbiah ◽  
Shichen Shen ◽  
Runpu Chen ◽  
Luke Terry ◽  
...  

Protein arginine methylation is a key post-translational modification in eukaryotes that modulates core cellular processes, including translation, morphology, transcription, and RNA fate. However, this has not been explored in Cryptococcus neoformans, a human-pathogenic basidiomycetous encapsulated fungus. We characterized the five protein arginine methyltransferases in C. neoformans and highlight Rmt5 as critical regulator of cryptococcal morphology and virulence. An rmt5∆ mutant was defective in thermotolerance, had a remodeled cell wall, and exhibited enhanced growth in an elevated carbon dioxide atmosphere and in chemically induced hypoxia. We revealed that Rmt5 interacts with post-transcriptional gene regulators, such as RNA-binding proteins and translation factors. Further investigation of the rmt5∆ mutant showed that Rmt5 is critical for the homeostasis of eIF2α and its phosphorylation state following 3-amino-1,2,4-triazole-induced ribosome stalling. RNA sequencing of one rmt5∆ clone revealed stable chromosome 9 aneuploidy that was ameliorated by complementation but did not impact the rmt5∆ phenotype. As a result of these diverse interactions and functions, loss of RMT5 enhanced phagocytosis by murine macrophages and attenuated disease progression in mice. Taken together, our findings link arginine methylation to critical cryptococcal cellular processes that impact pathogenesis, including post-transcriptional gene regulation by RNA- binding proteins.


Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 264
Author(s):  
Mengyao Qin ◽  
Yu Xin ◽  
Yong Bian ◽  
Xuan Yang ◽  
Tao Xi ◽  
...  

Pregnane X receptor (PXR) is a member of the nuclear receptor superfamily that is activated by a variety of endogenous metabolites or xenobiotics. Its downstream target genes are involved in metabolism, inflammation and processes closely related to cancer. However, the stability regulation of PXR protein resulting from post-translational modification is still largely undefined. In the present study, primary mouse hepatocytes, hepatoma HepG2 cells and HEK 293T cells were used to investigate gene expression and protein interactions. The role of kinases was evaluated by RNA interference and overexpression constructs with or without PXR phosphorylation site mutations. The activity of CYP3A4 and P-gp was determined by enzymatic and substrate accumulation assays. It was found that E3 ubiquitin ligase TRIM21 mediates the ubiquitination and degradation of PXR and plays an important role in regulating the activity of PXR. On this basis, PXR phosphorylation-associated kinases were evaluated regarding regulation of the stability of PXR. We found cyclin dependent kinase 2 (CDK2) exclusively phosphorylates PXR at Ser350, promotes its disassociation with Hsp90/DNAJC7, and leads to subsequent TRIM21-mediated PXR ubiquitination and degradation. As well-known CDK inhibitors, dinaciclib and kenpaullone stabilize PXR and result in elevated expression and activity of PXR-targeted DMETs, including carboxylesterases, CYP3A4 and P-gp. The suppressed degradation of PXR by CDK2 inhibitors denotes dinaciclib-induced promotion of PXR-targeted genes. The findings of CDK2-mediated PXR degradation indicate a wide range of potential drug–drug interactions during clinical cancer therapy using CDK inhibitors and imply an alternative direction for the development of novel PXR antagonists.


2022 ◽  
Vol 221 (2) ◽  
Author(s):  
Gregory C. Addicks ◽  
Hongbo Zhang ◽  
Dongryeol Ryu ◽  
Goutham Vasam ◽  
Alexander E. Green ◽  
...  

Protein lysine acetylation is a post-translational modification that regulates protein structure and function. It is targeted to proteins by lysine acetyltransferases (KATs) or removed by lysine deacetylases. This work identifies a role for the KAT enzyme general control of amino acid synthesis protein 5 (GCN5; KAT2A) in regulating muscle integrity by inhibiting DNA binding of the transcription factor/repressor Yin Yang 1 (YY1). Here we report that a muscle-specific mouse knockout of GCN5 (Gcn5skm−/−) reduces the expression of key structural muscle proteins, including dystrophin, resulting in myopathy. GCN5 was found to acetylate YY1 at two residues (K392 and K393), disrupting the interaction between the YY1 zinc finger region and DNA. These findings were supported by human data, including an observed negative correlation between YY1 gene expression and muscle fiber diameter. Collectively, GCN5 positively regulates muscle integrity through maintenance of structural protein expression via acetylation-dependent inhibition of YY1. This work implicates the role of protein acetylation in the regulation of muscle health and for consideration in the design of novel therapeutic strategies to support healthy muscle during myopathy or aging.


2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Markus Schick ◽  
Le Zhang ◽  
Sabine Maurer ◽  
Hans Carlo Maurer ◽  
Konstandina Isaakaidis ◽  
...  

AbstractSUMOylation is a post-translational modification of proteins that regulates these proteins’ localization, turnover or function. Aberrant SUMOylation is frequently found in cancers but its origin remains elusive. Using a genome-wide transposon mutagenesis screen in a MYC-driven B-cell lymphoma model, we here identify the SUMO isopeptidase (or deconjugase) SENP6 as a tumor suppressor that links unrestricted SUMOylation to tumor development and progression. Notably, SENP6 is recurrently deleted in human lymphomas and SENP6 deficiency results in unrestricted SUMOylation. Mechanistically, SENP6 loss triggers release of DNA repair- and genome maintenance-associated protein complexes from chromatin thereby impairing DNA repair in response to DNA damages and ultimately promoting genomic instability. In line with this hypothesis, SENP6 deficiency drives synthetic lethality to Poly-ADP-Ribose-Polymerase (PARP) inhibition. Together, our results link SENP6 loss to defective genome maintenance and reveal the potential therapeutic application of PARP inhibitors in B-cell lymphoma.


2022 ◽  
Vol 4 (1) ◽  
Author(s):  
Yu Wang ◽  
Nan Yang ◽  
Yunna Zheng ◽  
Jiaolin Yue ◽  
Vijai Bhadauria ◽  
...  

AbstractUbiquitination is a vital protein post-translational modification (PTM) prevalent in eukaryotes. This modification regulates multiple cellular processes through protein degradation mediated by the 26S proteasome or affecting protein–protein interaction and protein localization. Magnaporthe oryzae causes rice blast disease, which is one of the most devastating crop diseases worldwide. In M. oryzae, ubiquitination plays important roles in growth, pathogenicity, stress response and effector-mediated plant-pathogen interaction. In this review, we summarize the roles of ubiquitination components in the above biological processes of M. oryzae, including single- or multi-subunit E3s, E2s, components of 26S proteasome and also deubiquitinating enzymes. The essential function of ubiquitination in plant-fungus interaction is also discussed. Moreover, this review presents several issues related to the ubiquitination system in M. oryzae, which need to be further explored in future researches.


2022 ◽  
Author(s):  
Michaela Fenckova ◽  
Villo Muha ◽  
Daniel Mariyappa ◽  
Marica Catinozzi ◽  
Ignacy Czajewski ◽  
...  

O-GlcNAcylation is a reversible co-/post-translational modification involved in a multitude of cellular processes. The addition and removal of O-GlcNAc modification is controlled by two conserved enzymes, O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase (OGA). Mutations in OGT have recently been discovered to cause a novel Congenital Disorder of Glycosylation (OGT-CDG) that is characterized by intellectual disability. The mechanisms by which OGT-CDG mutations affect cognition remain unclear. We manipulated O-GlcNAc transferase and O-GlcNAc hydrolase activity in Drosophila and demonstrate an important role of O-GlcNAcylation in habituation learning and synaptic development at the larval neuromuscular junction. Introduction of patient-specific missense mutations into Drosophila O-GlcNAc transferase using CRISPR/Cas9 gene editing, leads to deficits in locomotor function and habituation learning. The habituation deficit can be corrected by blocking O-GlcNAc hydrolysis, indicating that OGT-CDG mutations affect cognitive function via reduced protein O-GlcNAcylation. This study establishes a critical role for O-GlcNAc cycling and disrupted O-GlcNAc transferase activity in cognitive dysfunction. These findings suggest that blocking O-GlcNAc hydrolysis is a potential treatment strategy for OGT-CDG.


Author(s):  
Lauren Eades ◽  
Michael Drozd ◽  
Richard M. Cubbon

Innate immune function is shaped by prior exposures in a phenomenon often referred to as ‘memory’ or ‘training’. Diverse stimuli, ranging from pathogen-associated molecules to atherogenic lipoproteins, induce long-lasting training, impacting on future responses, even to distinct stimuli. It is now recognised that epigenetic modifications in innate immune cells, and their progenitors, underpin these sustained behavioural changes, and that rewired cellular metabolism plays a key role in facilitating such epigenetic marks. Oxygen is central to cellular metabolism, and cells exposed to hypoxia undergo profound metabolic rewiring. A central effector of these responses are the hypoxia inducible factors (or HIFs), which drive transcriptional programmes aiming to adapt cellular homeostasis, such as by increasing glycolysis. These metabolic shifts indirectly promote post-translational modification of the DNA-binding histone proteins, and also of DNA itself, which are retained even after cellular oxygen tension and metabolism normalise, chronically altering DNA accessibility and utilisation. Notably, the activity of HIFs can be induced in some normoxic circumstances, indicating their broad importance to cell biology, irrespective of oxygen tension. Some HIFs are implicated in innate immune training and hypoxia is present in many disease states, yet many questions remain about the association between hypoxia and training, both in health and disease. Moreover, it is now appreciated that cellular responses to hypoxia are mediated by non-HIF pathways, suggesting that other mechanisms of training may be possible. This review sets out to define what is already known about the topic, address gaps in our knowledge, and provide recommendations for future research.


2022 ◽  
Author(s):  
Xuxue Guo ◽  
Mei Huang ◽  
Haonan Zhang ◽  
Qianhui Chen ◽  
Ying Hu ◽  
...  

Abstract BackgroundThe critical role of thioredoxin-interacting protein (TXNIP) in cellular sulfhydryl redox homeostasis and inflammasome activation is already widely known, however, no pan-cancer analysis is currently available. MethodsWe thus first explored the potential roles of TXNIP across thirty-three tumors mainly based on The Cancer Genome Atlas and Gene Expression Omnibus datasets. ResultsTXNIP is lowly expressed in most cancers, and distinct associations exist between TXNIP expression and the prognosis of tumor patients. TXNIP expression was associated with tumor mutational burden, microsatellite instability, mismatch repair genes, tumor infiltrating immune cell abundance as well as cancer-associated fibroblasts. Moreover, ubiquitin mediated proteolysis, protein post-translational modification and other related pathways were involved in the functional mechanisms of TXNIP. ConclusionsOur first pan-cancer study offers a relatively comprehensive understanding of the carcinostatic roles of TXNIP across different tumors. And this molecule may be considered as a potential immunological and prognostic biomarker.


2022 ◽  
Author(s):  
Tobias V Lanz ◽  
R Camille Brewer ◽  
Peggy P Ho ◽  
Kevin M Jude ◽  
Daniel Fernandez ◽  
...  

Abstract Multiple sclerosis (MS) is a heterogenous autoimmune disease in which autoreactive lymphocytes attack the myelin sheath of the central nervous system (CNS). B lymphocytes in the cerebrospinal fluid (CSF) of MS patients contribute to inflammation and secrete oligoclonal immunoglobulins. Epstein-Barr virus (EBV) infection has been linked to MS epidemiologically, but its pathological role remains unclear. Here we demonstrate high-affinity molecular mimicry between the EBV transcription factor EBNA1 and the CNS protein GlialCAM, and provide structural and in-vivo functional evidence for its relevance. A cross-reactive CSF-derived antibody was initially identified by single-cell sequencing of the paired-chain B cell repertoire of MS blood and CSF, followed by protein microarray-based testing of recombinantly expressed CSF-derived antibodies against MS-associated viruses. Sequence analysis, affinity measurements, and the crystal structure of the EBNA1-peptide epitope in complex with the autoreactive Fab fragment allowed for tracking the development of the naïve EBNA1-restricted antibody to a mature EBNA1/GlialCAM cross-reactive antibody. Molecular mimicry is facilitated by a post-translational modification of GlialCAM. EBNA1 immunization exacerbates the mouse model of MS and anti-EBNA1/GlialCAM antibodies are prevalent in MS patients. Our results provide a mechanistic link for the association between MS and EBV, and could guide the development of novel MS therapies.


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