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The quest for new robust bacterial monoamine oxidases
- The FEBS Journal
-  27 November 2023
Graphical Abstract

Microbial enzymes are versatile, cost-effective, and sustainable tools, making them a preferred choice for enzymatic processes. Santema and colleagues harnessed AlphaFold, a cutting-edge structure prediction tool, to discover new thermophilic monoamine oxidases (MAO) that could be relevant for drug development and use in biotechnology fields. This bacterial enzyme, paired with recent advancements in enzyme engineering, has the potential to meet the biotech sector's need for customized enzymes.
Comment on: https://doi.org/10.1111/febs.16973
NTNH protein: more than a bodyguard for botulinum neurotoxins
- The FEBS Journal
-  27 November 2023
Graphical Abstract

Nontoxic nonhemagglutinin (NTNH) is a protein co-secreted with botulinum neurotoxin (BoNT) by bacteria. A new cryo-EM structure of a BoNT-like toxin from Weissella oryzae (BoNT/Wo) in complex with its NTNH suggests that NTNH/Wo plays a conserved role as canonical NTNHs in stabilizing and protecting BoNTs. Furthermore, NTNH/Wo displays some unique structural features including two extra Big domains, suggesting NTNH/Wo may be involved in host targeting and play additional roles during BoNT intoxication.
Comment on: https://doi.org/10.1111/febs.16964.
Correction
- The FEBS Journal
-  23 November 2023
Expression of Concern: Curcumin upregulates phosphatase and tensin homologue deleted on chromosome 10 through microRNA‐mediated control of DNA methylation—a novel mechanism suppressing liver fibrosis
- The FEBS Journal
-  21 November 2023
Too big not to fail: emerging evidence for size‐induced senescence
- The FEBS Journal
-  20 November 2023
Graphical Abstract

Senescence is a permanent state of cell cycle arrest and plays an important role in development, aging, and cancer biology. Although senescent cells are known to be larger than proliferative cells, recent research has revealed that increased cell size is not only a consequence but also a cause of permanent cell cycle exit. This review illustrates how excess cell size alters normal cell physiology and contributes to senescence induction.
Tumor immune evasion: insights from CRISPR screens and future directions
- The FEBS Journal
-  16 November 2023
Graphical Abstract

Despite the clinical success of cancer immunotherapies including immune checkpoint blockade and adoptive cellular therapies, many patients do not respond or ultimately relapse. We discuss the use of CRISPR/Cas-based approaches to identify mechanisms of tumor immune evasion and avenues to sensitize cancers to destruction by the immune system. We provide a perspective on screening approaches and review the further development of technologies to improve such approaches and discovery capability.
A poly-proline II helix in YadA from Yersinia enterocolitica serotype O:9 facilitates heparin binding through electrostatic interactions
- The FEBS Journal
-  12 November 2023
Graphical Abstract

YadAO:9, the major adhesin of Yersinia enterocolitica serotype O:9, harbors an N-terminal poly-proline II helix that facilitates heparin binding. Binding is based on electrostatic interactions between basic residues within the YadAO:9 motif and sulfate groups of heparin. This interaction is important for host cell binding: YadAO:9-mediated adhesion to cells deficient in heparan sulfate production is significantly reduced.
The influence of a copper efflux pump in Histoplasma capsulatum virulence
- The FEBS Journal
-  11 November 2023
Graphical Abstract

Histoplasma capsulatum elevates Crp1 expression in the presence of copper in vitro or in macrophage infection. Copper chelation hampered macrophage ability to control the fungus, while fungal burden decreases in copper-treated immune cells. ATP7a silencing (phagosome copper pump) also caused increased fungal burden. H. capsulatum CRP1-knockdown strains attenuated virulence. These data show that copper increase is a strategy for phagocytes to control H. capsulatum, and Crp1 is responsible for H. capsulatum virulence.
Cytosolic phospholipase A2 regulates lipid homeostasis under osmotic stress through PPARγ
- The FEBS Journal
-  10 November 2023
Graphical Abstract

Hyperosmolality induces cPLA2 expression and translocation from the cytosol to intracellular membranes. Once activated, cPLA2 releases arachidonic acid (AA) from membrane glycerophospholipids. Free AA can be converted to prostaglandins (PG) through the COX2 enzyme or can activate the PPARγ nuclear receptor, which in turn induces triglyceride (TG) synthesis and accumulation in lipid droplets. TG synthesis contributes to osmoprotection of renal epithelial cells under osmotic stress.
Comparative analysis of PDZ‐binding motifs in the diacylglycerol kinase family
- The FEBS Journal
-  9 November 2023
Graphical Abstract

Diacylglycerol kinases (DGKs) are crucial proteins that regulate the levels of key signaling lipids. Many of these enzymes contain a C-terminal peptide region that sequentially corresponds to a PDZ domain recognition motif (PBM). In this study, the authors comprehensively studied the PDZ-PBM interactome of these enzymes using different interactomic approaches, supported by evolutionary conservation analyses. They were able to reveal functional differences between PBMs of different types of DGKs.
Leucine zipper protein 1 (LUZP1) regulates the constriction velocity of the contractile ring during cytokinesis
- The FEBS Journal
-  27 November 2023
Deciphering the structure and mechanism‐of‐action of computer‐designed mastoparan peptides
- The FEBS Journal
-  24 November 2023
Hydrolytic activity of yeast oligosaccharyltransferase is enhanced when misfolded proteins accumulate in the endoplasmic reticulum
- The FEBS Journal
-  24 November 2023
Genetic Mechanisms of Multiciliated Cell Development: From Fate Choice to Differentiation in Zebrafish and Other Models
- The FEBS Journal
-  23 November 2023
The chemokines CCL5 and CXCL12 exhibit high‐affinity binding to N‐terminal peptides of the non‐cognate receptors CXCR4 and CCR5, respectively
- The FEBS Journal
-  23 November 2023
Gasdermin‐B (GSDMB) takes center stage in antibacterial defense, inflammatory diseases, and cancer
- The FEBS Journal
-  23 November 2023
The Crosstalk between ILC3s and Adaptive Immunity in Diseases
- The FEBS Journal
-  22 November 2023
Molecular characterization of the craniosynostosis‐associated interleukin‐11 receptor variants p.T306_S308dup and p.E364_V368del
- The FEBS Journal
-  22 November 2023
RRM1 and PAB domains of translation initiation factor eIF4G (Tif4631p), play a crucial role in the nuclear degradation of export-defective mRNAs in Saccharomyces cerevisiae
- The FEBS Journal
-  22 November 2023
Butyrate functions as a histone deacetylase inhibitor to protect pancreatic beta cells from IL‐1β‐induced dysfunction
- The FEBS Journal
-  20 November 2023
A CRISPR/Cas9-based multicopy integration system for protein production in Aspergillus niger
- The FEBS Journal
-  5127-5140
-  19 June 2023
Graphical Abstract

Using an iterative two-step CRISPR/Cas9-mediated genome editing approach, 10 loci were modified to generate multi-copy strains expressing the gene of interest in the filamentous fungus Aspergillus niger. The selected loci for gene disruption represent highly expressed genes encoding extracellular proteins including the major starch degrading enzymes and proteases. We successfully used the expression platform to generate multicopy A. niger strains producing the Penicillium expansum PatE protein.
Efficient CRISPR/Cas9 mediated large insertions using long single-stranded oligonucleotide donors in C. elegans
- The FEBS Journal
-  4429-4439
-  31 May 2023
Graphical Abstract

Highly efficient CRISPR/Cas9 genome editing in Caenorhabditis elegans has been facilitated by using single-stranded oligonucleotide donors as repair templates. However, insertion of larger sequences remains challenging. Here, Matthew Eroglu, Bin Yu and Brent Derry simplified the generation of long ssDNA as donors in CRISPR/Cas9. High ssDNA yields are rapidly generated using a standard PCR followed by an enzymatic digest with lambda exonuclease. The insertion frequency for these long ssDNA donors is remarkably higher than dsDNA. This can be leveraged to simultaneously generate multiple large insertions and successful edits. This approach enables highly efficient insertion of longer sequences using CRISPR/Cas9 in C. elegans.
Skeletal muscle-enriched miRNAs are highly unstable in vivo and may be regulated in a Dicer-independent manner
- The FEBS Journal
-  31 July 2023
Graphical Abstract

We investigated the half-lives of miRNAs in adult skeletal muscle with an in vivo metabolic labeling approach and a genetic mouse model. In vivo metabolic labeling and chasing of miRNAs revealed that the half-lives of skeletal-muscle-enriched miRNAs were 11–20 h. Furthermore, the miR-23a levels decreased rapidly in the skeletal muscle of mice with an inducible loss of miR-23 clusters. These findings suggest that the half-lives of miRNAs were relatively short.
Nicotinamide riboside activates SIRT5 deacetylation
- The FEBS Journal
-  4762-4776
-  8 June 2023
Graphical Abstract

SIRT5, one of the seven human sirtuins, plays vital roles in maintaining neuronal viability, cardiac health and ageing. The deacetylase activity of SIRT5 can be selectively activated by nicotinamide riboside (NR), a small molecule metabolite involved in NAD+ biosynthesis. Characterization of the biochemical mechanism of NR activation suggests a putative binding site and also provides basis for further activator development.
Applications of fluorescent protein tagging in structural studies of membrane proteins
- The FEBS Journal
-  20 July 2023
Graphical Abstract

Fluorescence-based size exclusion chromatography (FSEC) is a versatile technique, which allows rapid screening of membrane proteins fused to fluorescent proteins for expression level, monodispersity, oligomerization state, and interprotein interactions without the need for purification. A modified FSEC, GFP-TS, is capable of high-throughput screening of lipid and ligand interactions with membrane proteins. FSEC technology has been instrumental in structural studies of diverse classes of membrane proteins through X-ray crystallography and Cryo-EM.
Identification of a diketopiperazine-based O-GlcNAc transferase inhibitor sensitizing hepatocellular carcinoma to CDK9 inhibition
- The FEBS Journal
-  4543-4561
-  29 May 2023
Graphical Abstract

The post-translational process O-GlcNAcylation is implicated in a variety of physiological processes and diseases, including hepatocellular carcinoma. Here, we identified HLY838, a novel diketopiperazine-based OGT inhibitor that induces a global decrease in cellular O-GlcNAcylation. HLY838 enhances the anti-HCC activity of CDK9 inhibitors both in vitro and in vivo by downregulating c-Myc and E2F1 expression. Our findings suggest that targeting O-GlcNAcylation with HLY838 may be an effective strategy to improve cancer therapy.
Hepatocyte reprogramming in liver regeneration: Biological mechanisms and applications
- The FEBS Journal
-  9 August 2023
Graphical Abstract

The liver is one of the few organs that retain the capability to regenerate in adult mammals. Hepatocytes play a crucial role in liver regeneration through reprogramming and expansion after injury. Here, we review the molecular mechanisms governing the remarkable plasticity of hepatocytes in various liver disorders, with a focus on injury-induced reprogramming, and highlight its potential therapeutic applications in chronic liver diseases and liver cancer.
Introduction of reversible cysteine ligation ability to the biliverdin‐binding cyanobacteriochrome photoreceptor
- The FEBS Journal
-  4999-5015
-  24 July 2023
Graphical Abstract

Site-saturation mutagenesis on the far-red/orange reversible AnPixJg2_BV4 cyanobacteriochrome photoreceptor succeeded in serendipitously obtaining a far-red/blue reversible variant molecule that acquired a Cys residue. The acquired Cys residue seemed to reversibly ligate to the chromophore to function as a “second Cys” at a unique position. The variant molecule obtained in this study expands our knowledge about the spectral tuning mechanism of CBCRs and contributes to tool development.
CD24 targeting with NK-CAR immunotherapy in testis, prostate, renal and (luminal-type) bladder cancer and identification of direct CD24 interaction partners
- The FEBS Journal
-  4864-4876
-  31 May 2023
Graphical Abstract

Alternative therapeutic options targeting urologic malignancies, such as germ cell tumours, as well as urothelial, renal and prostate carcinomas, are still urgently needed. The membrane protein CD24 represents a promising immunotherapeutical approach. In this study, Daniel Nettersheim and colleagues demonstrate the therapeutic efficacy of using NK-CD24-CAR cells for the treatment of CD24+ urologic malignancies in vitro. Immunoprecipitation followed by mass spectometry analyses identified bona fide interaction partners of CD24 to be involved in posttranslational modifications, cell adhesion, and metabolic processes. Moreover, the glycosylation pattern of CD24 and the SOX2-dependent regulation of expression were investigated to further enlighten its molecular function.
Structure elucidation and characterization of patulin synthase, insights into the formation of a fungal mycotoxin
- The FEBS Journal
-  5114-5126
-  27 June 2023
Graphical Abstract

Patulin synthase (PatE) from Penicillium expansum is a flavin-dependent enzyme that catalyses the last step in the biosynthesis of the mycotoxin patulin. The patE gene was expressed in Aspergillus niger allowing purification and characterization of PatE. This confirmed that PatE is active not only on the proposed patulin precursor ascladiol but also on several aromatic alcohols including 5-hydroxymethylfurfural. By elucidating its crystal structure, details on its catalytic mechanism were revealed.
Targeting cellular senescence with senotherapeutics: senolytics and senomorphics
- The FEBS Journal
-  1362-1383
-  11 January 2022
Graphical Abstract

Cellular senescence, a critical hallmark of ageing, has been shown to drive many age-associated chronic diseases. Senescent cells (SnCs) up-regulate pathways associated with evasion of apoptosis, survival, senescence-associated secretory phenotype (SASP) development and others that are targeted using senotherapeutics. Senotherapeutics selectively target SnCs for their clearance (senolytics) or suppression of their SASP (senomorphics). Many studies have demonstrated the benefit of senotherapeutic treatment for the extension of health and lifespan.
The blood–retina barrier in health and disease
- The FEBS Journal
-  878-891
-  18 December 2021
Graphical Abstract

The inner blood–retina barrier (iBRB) refers to the properties of endothelial cells associated with the blood vessels of the inner retina. These cells strictly regulate entry and exit from the retina and perturbations in their function have detrimental effects on vision and lead to conditions such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). This review provides a succinct overview of BRB breakdown-associated retinal conditions and the putative underlying mechanisms of disease.
Lipid metabolism and Alzheimer's disease: clinical evidence, mechanistic link and therapeutic promise
- The FEBS Journal
-  1420-1453
-  7 January 2022
Graphical Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease with multifactorial etiology, intersecting risk factors, and a lack of disease-modifying therapeutics. In this review, converging clinical evidence defining lipid dyshomeostasis in early stages of AD is summarized followed by discussions on mechanisms by which lipid metabolism contributes to pathogenesis and modifies disease risk. Furthermore, existing and potential lipid-targeting therapeutic strategies are reviewed.
Cellular senescence: all roads lead to mitochondria
- The FEBS Journal
-  1186-1202
-  20 January 2022
Graphical Abstract

Mitochondria play a central role in the development of cellular senescence. Senescence is characterized by several mitochondrial functional changes such as a decrease in OXPHOS, reduced levels of NAD+ and ATP, and accumulation of TCA cycle metabolites, DAMPs, and ROS. Here, we provide an overview of the recent findings demonstrating how these mitochondrial changes can contribute to the senescence-associated growth arrest and the SASP.
A guide to studying protein aggregation
- The FEBS Journal
-  554-583
-  4 December 2021
Graphical Abstract

The accumulation of un- or misfolded proteins can lead to the formation of amorphous or ordered aggregates. Protein aggregation is often associated with human diseases and unravelling its underlying mechanism is critical for the development of diagnostic methods or treatments. However, investigating protein aggregation is challenging due to its complex and dynamic nature. Here, we summarized some popular methods to study the various aspects and steps involved in protein aggregation.
Nrf2 and oxidative stress in liver ischemia/reperfusion injury
- The FEBS Journal
-  5463-5479
-  30 December 2021
Graphical Abstract

Nrf2 activates different cellular mechanisms in response to ischemia-reperfusion (IR) injury in liver. IR is a major cause of graft loss and dysfunction in clinical transplantation and organ resection. During the IR process, ROS generation leads oxidative stress, inflammation and mitochondrial dysfunction. After Nrf2 activation, the downstream antioxidant upregulation can act as a primary cellular defense and help to promote hepatic recovery during IR.
Ferroptosis: regulation by competition between NRF2 and BACH1 and propagation of the death signal
- The FEBS Journal
-  1688-1704
-  2 February 2022
Graphical Abstract

Ferroptosis is regulated by two transcription factors, NRF2 and BACH1, as its suppressor and promoter respectively. Here, we reviewed how these factors regulate execution of ferroptosis by changing ferroptosis-related metabolites (labile iron, glutathione and ubiquinol), lipid metabolism and cell differentiation. Ferroptosis is elaborately regulated by the competition of NRF2 and BACH1. Death signal is secreted from ferroptotic cells to surrounding cells, and its nature is also discussed.
The role of cellular senescence and SASP in tumour microenvironment
- The FEBS Journal
-  1348-1361
-  2 February 2022
Graphical Abstract

Cellular senescence functions as a tumour suppressive mechanism, inhibiting the proliferation of cancer-prone cells. In precancerous cells, major autocrine/paracrine tumour-suppressive effects promote senescence surveillance by immune cells. However, in advanced cancer, the altered secretory profile of senescent cells, termed senescence-associated secretory phenotype (SASP), enables the formation of tumour-promoting microenvironments. While SASP and its effects on tumorigenesis are context dependent, deciphering the mechanisms underlying such diversity will allow targeting SASP effectively for cancer therapy.
A recent update on small‐molecule kinase inhibitors for targeted cancer therapy and their therapeutic insights from mass spectrometry‐based proteomic analysis
- The FEBS Journal
-  2845-2864
-  21 March 2022
Graphical Abstract

Following the ground-breaking discovery of imatinib for the treatment of chronic myeloid leukaemia, there has been increasing interest in harnessing kinases as drug targets for cancer. In this article, we provide an update on the current progress with small-molecule kinase inhibitors that have been approved for clinical use. We then discuss the application of mass spectrometry-based proteomics strategies as well as the challenges and outlook for kinase inhibitor research.
BRD4 and MYC: power couple in transcription and disease
- The FEBS Journal
-  4820-4842
-  22 July 2022
Graphical Abstract

MYC and BRD4 play central roles as chromatin and transcriptional regulators in controlling growth, development, stress responses, metabolism and genome stability. This review discusses MYC and BRD4 regulation, their overlapping roles in various cellular processes and how their functional or regulatory impairment leads to disease. Understanding this complex interplay between the two proteins can inform treatment modalities that will effectively counter their pathological effects while preserving normal cellular function.