Role Of Post-translational Modifications Research Articles

UBL3 Interacts with PolyQ-Expanded Huntingtin Fragments and Modifies Their Intracellular Sorting.

UBL3 (Ubiquitin-like 3) is a protein that plays a crucial role in post-translational modifications, particularly in regulating protein transport within small extracellular vesicles. While previous research has predominantly focused on its interactions with α-synuclein, this study investigates UBL3's role in Huntington's disease (HD). HD is characterized by movement disorders and cognitive impairments, with its pathogenesis linked to toxic, polyglutamine (polyQ)-expanded mutant huntingtin fragments (mHTT). However, the mechanisms underlying the interaction between UBL3 and mHTT remain poorly understood. To elucidate this relationship, we performed hematoxylin and eosin (HE) staining and immunohistochemistry (IHC) on postmortem brain tissue from HD patients. Gaussia princeps-based split-luciferase complementation assay and co-immunoprecipitation were employed to confirm the interaction between UBL3 and mHTT. Additionally, we conducted a HiBiT lytic detection assay to assess the influence of UBL3 on the intracellular sorting of mHTT. Finally, immunocytochemical staining was utilized to validate the colocalization and distribution of these proteins. Our findings revealed UBL3-positive inclusions in the cytoplasm and nuclei of neurons throughout the striatum of HD patients. We discovered that UBL3 colocalizes and interacts with mHTT and modulates its intracellular sorting. These results suggest that UBL3 may play a significant role in the interaction and sorting of mHTT, contributing to the understanding of its potential implications in the pathophysiology of Huntington's disease.

Phosphorylation-driven epichaperome assembly is a regulator of cellular adaptability and proliferation

The intricate network of protein-chaperone interactions is crucial for maintaining cellular function. Recent discoveries have unveiled the existence of specialized chaperone assemblies, known as epichaperomes, which serve as scaffolding platforms that orchestrate the reconfiguration of protein-protein interaction networks, thereby enhancing cellular adaptability and proliferation. This study explores the structural and regulatory aspects of epichaperomes, with a particular focus on the role of post-translational modifications (PTMs) in their formation and function. A key finding is the identification of specific PTMs on HSP90, particularly at residues Ser226 and Ser255 within an intrinsically disordered region, as critical determinants of epichaperome assembly. Our data demonstrate that phosphorylation of these serine residues enhances HSP90’s interactions with other chaperones and co-chaperones, creating a microenvironment conducive to epichaperome formation. Moreover, we establish a direct link between epichaperome function and cellular physiology, particularly in contexts where robust proliferation and adaptive behavior are essential, such as in cancer and pluripotent stem cell maintenance. These findings not only provide mechanistic insights but also hold promise for the development of novel therapeutic strategies targeting chaperone assemblies in diseases characterized by epichaperome dysregulation, thereby bridging the gap between fundamental research and precision medicine.

Post-translational modification in the pathogenesis of vitiligo.

Vitiligo is a chronic dermatological condition marked by the loss of skin pigmentation. Its complex etiology involves multiple factors and has not been completely elucidated. Protein post-translational modification pathways have been proven to play a significant role in inflammatory skin diseases, yet research in the context of vitiligo remains limited. This review focuses on the role of post-translational modifications in vitiligo pathogenesis, especially their impact on cellular signaling pathways related to immune response and melanocyte survival. Current therapeutic strategies targeting these pathways are discussed, emphasizing the potential for novel treatments in vitiligo management.

A ubiquitin-mediated post-translational degradation of Cyp51A contributes to a novel azole resistance mode in Aspergillus fumigatus

The airborne fungus Aspergillus fumigatus is a major pathogen that poses a serious health threat to humans by causing aspergillosis. Azole antifungals inhibit sterol 14-demethylase (encoded by cyp51A), an enzyme crucial for fungal cell survival. However, the most common mechanism of azole resistance in A. fumigatus is associated with the mutations in cyp51A and tandem repeats in its promoter, leading to reduced drug-enzyme interaction and overexpression of cyp51A. It remains unknown whether post-translational modifications of Cyp51A contribute to azole resistance. In this study, we report that the Cyp51A expression is highly induced upon exposure to itraconazole, while its ubiquitination level is significantly reduced by itraconazole. Loss of the ubiquitin-conjugating enzyme Ubc7 confers resistance to multiple azole antifungals but hinders hyphal growth, conidiation, and virulence. Western blot and immunoprecipitation assays show that deletion of ubc7 reduces Cyp51A degradation by impairing its ubiquitination, thereby leading to drug resistance. Most importantly, the overexpression of ubc7 in common environmental and clinical azole-resistant cyp51A isolates partially restores azole sensitivity. Our findings demonstrate a non-cyp51A mutation-based resistance mechanism and uncover a novel role of post-translational modification in contributing to azole resistance in A. fumigatus.

α2,6 sialylation distinguishes a novel active state in CD4+ and CD8+ cells during acute Toxoplasma gondii infection.

Toxoplasmosis is a worldwide parasitosis that is usually asymptomatic; cell-mediated immunity, particularly T cells, is a crucial mediator of the immune response against this parasite. Membrane protein expression has been studied for a long time in T lymphocytes, providing vital information to determine functional checkpoints. However, less is known about the role of post-translational modifications in T cell function. Glycosylation plays essential roles during maturation and function; particularly, sialic acid modulation is determinant for accurate T cell regulation of processes like adhesion, cell-cell communication, and apoptosis induction. Despite its importance, the role of T cell sialylation during infection remains unclear. Herein, we aimed to evaluate whether different membrane sialylation motifs are modified in T cells during acute Toxoplasma gondii infection using different lectins. To this end, BALB/c Foxp3EGFP mice were infected with T. gondii, and on days 3, 7, and 10 post-infection, splenocytes were obtained to analyze conventional (Foxp3-) CD4+ and CD8+ populations by flow cytometry. Among the different lectins used for analysis, only Sambucus nigra lectin, which detects sialic acid α2,6 linkages, revealed two distinctive populations (SNBright and SN-/Dim) after infection. Further characterization of CD4+ and CD8+ SN-/Dim lymphocytes showed that these are highly activated cells, with a TEf/EM or TCM phenotype that produce high IFN-γ levels, a previously undescribed cell state. This work demonstrates that glycan membrane analysis in T cells reveals previously overlooked functional states by evaluating only protein expression.

H3K18 Lactylation Potentiates Immune Escape of Non-Small Cell Lung Cancer.

The recently discovered epigenetic modification lysine lactylation (Kla) contributes to tumor development and progression in several types of cancer. In addition to the tumor-intrinsic effects, histone lactylation may mediate tumor microenvironment remodeling and immune evasion. Here, we observed elevated pan Kla and H3K18la levels in non-small cell lung cancer (NSCLC) tissues, which was positively correlated with poor patient prognosis. Interruption of glycolysis by 2-DG and oxamate treatment and silencing of LDHA and LDHB reduced H3K18la levels and circumvented immune evasion of NSCLC cells by enhancing CD8+ T cell cytotoxicity. Mechanistically, H3K18la directly activated the transcription of POM121, which enhanced MYC nuclear transport and direct binding to the CD274 promoter to induce PD-L1 expression. In a mouse NSCLC xenograft model, combination therapy with a glycolysis inhibitor and an anti-PD-1 antibody induced intratumoral CD8+ T cell function and exhibited strong anti-tumor efficacy. Overall, this work revealed that H3K18la potentiates the immune escape of NSCLC cells by activating the POM121/MYC/PD-L1 pathway, which offers insight into the role of post-translational modifications in carcinogenesis and provides a rationale for developing an epigenetic-targeted strategy for treating NSCLC.

A de novo ARIH2 gene mutation was detected in a patient with autism spectrum disorders and intellectual disability

E3 ubiquitin protein ligase encoded by ARIH2 gene catalyses the ubiquitination of target proteins and plays a crucial role in posttranslational modifications across various cellular processes. As prior documented, mutations in genes involved in the ubiquitination process are often associated with autism spectrum disorder (ASD) and/or intellectual disability (ID). In the current study, a de novo heterozygous mutation was identified in the splicing intronic region adjacent to the last exon of the ARIH2 gene using whole exome sequencing (WES). We hypothesize that this mutation, found in an ASD/ID patient, disrupts the protein Ariadne domain which is involved in the autoinhibition of ARIH2 enzyme. Predictive analyses elucidated the implications of the novel mutation in the splicing process and confirmed its autosomal dominant inheritance model. Nevertheless, we cannot exclude the possibility that other genetic factors, undetectable by WES, such as mutations in non-coding regions and polygenic risk in inter-allelic complementation, may contribute to the patient's phenotype. This work aims to suggest potential relationship between the detected mutation in ARIH2 gene and both ASD and ID, even though functional studies combined with new sequencing approaches will be necessary to validate this hypothesis.

HDAC6-mediated deacetylation of FLOT2 maintains stability and tumorigenic function of FLOT2 in nasopharyngeal carcinoma.

Flotillin-2 (FLOT2) is a prototypical oncogenic and a potential target for cancer therapy. However, strategies for targeting FLOT2 remain undefined. Post-translational modifications are crucial for regulating protein stability, function, and localization. Understanding the mechanisms and roles of post-translational modifications is key to developing targeted therapies. This study aims to investigate the regulation and function of lysine acetylation of FLOT2 in nasopharyngeal carcinoma, providing new insights for targeting FLOT2 in cancer intervention. The PhosphoSitePlus database was used to analyze the lysine acetylation sites of FLOT2, and a lysine acetylation site mutation of FLOT2 [FLOT2 (K211R)] was constructed. Nasopharyngeal carcinoma cells were treated with histone deacetylase (HDAC) inhibitor trichostatin A (TSA) and Sirt family deacetylase inhibitor nicotinamide (NAM). TSA-treated human embryonic kidney (HEK)-293T were transfected with FLOT2 mutant plasmids. Co-immunoprecipitation (Co-IP) was used to detect total acetylation levels of FLOT2 and the effects of specific lysine (K) site mutations on FLOT2 acetylation. Western blotting was used to detect FLOT2/FLAG-FLOT2 protein expression in TSA-treated nasopharyngeal carcinoma cells transfected with FLOT mutant plasmids, and real-time reverse transcription PCR (real-time RT-PCR) was used to detect FLOT2 mRNA expression. Nasopharyngeal carcinoma cells were treated with TSA combined with MG132 or chloroquine (CQ) to analyze FLOT2 protein expression. Cycloheximide (CHX) was used to treat HEK-293T cells transfected with FLAG-FLOT2 (WT) or FLAG-FLOT2(K211R) plasmids to assess protein degradation rates. The BioGrid database was used to identify potential interactions between FLOT2 and HDAC6, which were validated by Co-IP. HEK-293T cells were co-transfected with FLAG-FLOT2 (WT)/FLAG-FLOT2 (K211R) and Vector/HDAC6 plasmids, and grouped into FLAG-FLOT2 (WT)+Vector, FLAG-FLOT2 (WT)+HDAC6, FLAG-FLOT2 (K211R)+Vector, and FLAG-FLOT2 (K211R)+HDAC6 to analyze the impact of K211R mutation on total lysine acetylation levels. In 6-0B cells, overexpression of FLOT2 (WT) and FLOT2 (K211R) was performed, and the biological functions of FLOT2 acetylation site mutants were assessed using cell counting kit-8 (CCK-8), colony formation, and Transwell invasion assays. The PhosphoSitePlus database indicated that FLOT2 has an acetylation modification at the K211 site. Co-IP confirmed significant acetylation of FLOT2, with TSA significantly increasing overall FLOT2 acetylation levels, while NAM had no effect. Mutation at the K211 site significantly reduced overall FLOT2 acetylation, unaffected by TSA. TSA decreased FLOT2 protein expression in nasopharyngeal carcinoma cells without affecting FLOT2 mRNA levels or FLOT2 (K211R) protein expression in transfected cells. The degradation rate of FLOT2 (K211R) protein was significantly slower than that of FLOT2 (WT). The proteasome inhibitor MG132 prevented TSA-induced FLOT2 degradation, while the lysosome inhibitor CQ did not. BioGrid data suggested a potential interaction between FLOT2 and HDAC6, confirmed by Co-IP. Knockdown of HDAC6 in nasopharyngeal carcinoma cells significantly increased FLOT2 acetylation; co-transfection of HDAC6 and FLAG-FLOT2 (WT) significantly decreased total lysine acetylation levels, whereas co-transfection of HDAC6 and FLAG-FLOT2 (K211R) had no effect. Knockdown of HDAC6 significantly reduced FLOT2 protein levels without affecting mRNA levels. MG132 prevented HDAC6-knockdown-induced FLOT2 degradation. Knockdown of HDAC6 significantly accelerated FLOT2 degradation. Nasopharyngeal carcinoma cells transfected with FLOT2 (K211R) showed significantly higher proliferation and invasion than those transfected with FLOT2 (WT). The K211 site of FLOT2 undergoes acetylation modification, and HDAC6 mediates deacetylation at this site, inhibiting proteasomal degradation of FLOT2 and maintaining its stability and tumor-promoting function in nasopharyngeal carcinoma.

Arginine methylation of caspase-8 controls life/death decisions in extrinsic apoptotic networks

Procaspase-8 is a key mediator of death receptor (DR)-mediated pathways. Recently, the role of post-translational modifications (PTMs) of procaspase-8 in controlling cell death has received increasing attention. Here, using mass spectrometry screening, pharmacological inhibition and biochemical assays, we show that procaspase-8 can be targeted by the PRMT5/RIOK1/WD45 methylosome complex. Furthermore, two potential methylation sites of PRMT5 on procaspase-8, R233 and R435, were identified in silico. R233 and R435 are highly conserved in mammals and their point mutations are among the most common mutations of caspase-8 in cancer. The introduction of mutations at these positions resulted in inhibitory effects on CD95L-induced caspase-8 activity, effector caspase activation and apoptosis. In addition, we show that procaspase-8 can undergo symmetric di-methylation. Finally, the pharmacological inhibition of PRMT5 resulted in the inhibitory effects on caspase activity and apoptotic cell death. Taken together, we have unraveled the additional control checkpoint in procaspase-8 activation and the arginine methylation network in the extrinsic apoptosis pathway.

Lactylation Modification in Cardiometabolic Disorders: Function and Mechanism.

Cardiovascular disease (CVD) is recognized as the primary cause of mortality and morbidity on a global scale, and developing a clear treatment is an important tool for improving it. Cardiometabolic disorder (CMD) is a syndrome resulting from the combination of cardiovascular, endocrine, pro-thrombotic, and inflammatory health hazards. Due to their complex pathological mechanisms, there is a lack of effective diagnostic and treatment methods for cardiac metabolic disorders. Lactylation is a type of post-translational modification (PTM) that plays a regulatory role in various cellular physiological processes by inducing changes in the spatial conformation of proteins. Numerous studies have reported that lactylation modification plays a crucial role in post-translational modifications and is closely related to cardiac metabolic diseases. This article discusses the molecular biology of lactylation modifications and outlines the roles and mechanisms of lactylation modifications in cardiometabolic disorders, offering valuable insights for the diagnosis and treatment of such conditions.

Bioactive Lignan Honokiol Alleviates Ovarian Oxidative Stress in Aging Laying Chickens by Regulating SIRT3/AMPK Pathway.

Aging is not only a key internal cause of age-related diseases in humans but also poses a threat to the productivity of farm animals with longer breeding cycles, such as laying chickens. Various measures were taken to prolong the laying period by reducing oxidative stress to improve poultry ovarian functions. Within the mitochondria, SIRT3, a member of the Sirtuin family, plays an important role in post-translational modifications and the regulation of protein activities involved in energy metabolism and oxidative response. This study aimed to investigate the alleviating effect of a bioactive lignan Honokiol (HKL) on oxidative stress in aging chicken ovaries in order to retard decline in egg production. The results showed that HKL treatment restored the abnormal balance between cell proliferation and apoptosis, and it enhanced the antioxidant capacity of the H2O2-induced small white follicles (SWFs) by activating the SIRT3/AMPK pathway. Moreover, HKL significantly increased total egg production, the number of yellow follicles, and the mRNA expression of yolk synthesis and deposition-related genes, serum estrogen, and antioxidant levels. These findings suggest that HKL holds promise in enhancing the egg productivity of aging laying chickens by promoting yolk deposition and reducing ovarian oxidative stress.

Crosstalk between ubiquitin ligases and ncRNAs drives cardiovascular disease progression.

Cardiovascular diseases (CVDs) are multifactorial chronic diseases and have the highest rates of morbidity and mortality worldwide. The ubiquitin-proteasome system (UPS) plays a crucial role in posttranslational modification and quality control of proteins, maintaining intracellular homeostasis via degradation of misfolded, short-lived, or nonfunctional regulatory proteins. Noncoding RNAs (ncRNAs, such as microRNAs, long noncoding RNAs, circular RNAs and small interfering RNAs) serve as epigenetic factors and directly or indirectly participate in various physiological and pathological processes. NcRNAs that regulate ubiquitination or are regulated by the UPS are involved in the execution of target protein stability. The cross-linked relationship between the UPS, ncRNAs and CVDs has drawn researchers' attention. Herein, we provide an update on recent developments and perspectives on how the crosstalk of the UPS and ncRNAs affects the pathological mechanisms of CVDs, particularly myocardial ischemia/reperfusion injury, myocardial infarction, cardiomyopathy, heart failure, atherosclerosis, hypertension, and ischemic stroke. In addition, we further envision that RNA interference or ncRNA mimics or inhibitors targeting the UPS can potentially be used as therapeutic tools and strategies.

Crosstalk of HDAC4, PP1, and GSDMD in controlling pyroptosis

Gasdermin D (GSDMD) functions as a pivotal executor of pyroptosis, eliciting cytokine secretion following cleavage by inflammatory caspases. However, the role of posttranslational modifications (PTMs) in GSDMD-mediated pyroptosis remains largely unexplored. In this study, we demonstrate that GSDMD can undergo acetylation at the Lysine 248 residue, and this acetylation enhances pyroptosis. We identify histone deacetylase 4 (HDAC4) as the specific deacetylase responsible for mediating GSDMD deacetylation, leading to the inhibition of pyroptosis both in vitro and in vivo. Deacetylation of GSDMD impairs its ubiquitination, resulting in the inhibition of pyroptosis. Intriguingly, phosphorylation of HDAC4 emerges as a critical regulatory mechanism promoting its ability to deacetylate GSDMD and suppress GSDMD-mediated pyroptosis. Additionally, we implicate Protein phosphatase 1 (PP1) catalytic subunits (PP1α and PP1γ) in the dephosphorylation of HDAC4, thereby nullifying its deacetylase activity on GSDMD. This study reveals a complex regulatory network involving HDAC4, PP1, and GSDMD. These findings provide valuable insights into the interplay among acetylation, ubiquitination, and phosphorylation in the regulation of pyroptosis, offering potential targets for further investigation in the field of inflammatory cell death.

Functional Roles of Furin in Cardio-Cerebrovascular Diseases.

Furin plays a major role in post-translational modification of several biomolecules, including endogenous hormones, growth factors, and cytokines. Recent reports have demonstrated the association of furin and cardio-cerebrovascular diseases (CVDs) in humans. This review describes the possible pathogenic contribution of furin and its substrates in CVDs. Early-stage hypertension and diabetes mellitus show a negative correlation with furin. A reduction in furin might promote hypertension by decreasing maturation of B-type natriuretic peptide (BNP) or by decreasing shedding of membrane (pro)renin receptor (PRR), which facilitates activation of the renin-angiotensin-aldosterone system (RAAS). In diabetes, furin downregulation potentially leads to insulin resistance by reducing maturation of the insulin receptor. In contrast, the progression of other CVDs is associated with an increase in furin, including dyslipidemia, atherosclerosis, ischemic stroke, myocardial infarction (MI), and heart failure. Upregulation of furin might promote maturation of membrane type 1-matrix metalloproteinase (MT1-MMP), which cleaves low-density lipoprotein receptor (LDLR), contributing to dyslipidemia. In atherosclerosis, elevated levels of furin possibly enhance maturation of several substrates related to inflammation, cell proliferation, and extracellular matrix (ECM) deposition and degradation. Neuronal cell death following ischemic stroke has also been shown to involve furin substrates (e.g., MT1-MMP, hepcidin, and hemojuvelin). Moreover, furin and its substrates, including tumor necrosis factor-α (TNF-α), endothelin-1 (ET-1), and transforming growth factor-β1 (TGF-β1), are capable of mediating inflammation, hypertrophy, and fibrosis in MI and heart failure. Taken together, this evidence provides functional significance of furin in CVDs and might suggest a potential novel therapeutic modality for the management of CVDs.

Role of Post-Translational Modifications in Colorectal Cancer Metastasis

Colorectal cancer (CRC) is one of the most common malignant tumors of the digestive tract. CRC metastasis is a multi-step process with various factors involved, including genetic and epigenetic regulations, which turn out to be a serious threat to CRC patients. Post-translational modifications (PTMs) of proteins involve the addition of chemical groups, sugars, or proteins to specific residues, which fine-tunes a protein’s stability, localization, or interactions to orchestrate complicated biological processes. An increasing number of recent studies suggest that dysregulation of PTMs, such as phosphorylation, ubiquitination, and glycosylation, play pivotal roles in the CRC metastasis cascade. Here, we summarized recent advances in the role of post-translational modifications in diverse aspects of CRC metastasis and its detailed molecular mechanisms. Moreover, advances in drugs targeting PTMs and their cooperation with other anti-cancer drugs, which might provide novel targets for CRC treatment and improve therapeutic efficacy, were also discussed.

The influence of estrogen on myocardial post-translational modifications and cardiac function in women.

The lifetime risk of heart failure (HF) is comparable in men and women; nevertheless, disparities exist in our understanding of how HF differs between sexes. Several differences in cardiac physiology exist between men and women including the propensity to develop specific HF phenotypes. Men are more likely to be diagnosed with HF failure with reduced ejection fraction, while women have a greater propensity to develop HF with preserved ejection fraction. The mechanisms responsible for these differences remain unclear. Post-translational modifications (PTMs) of myofilament proteins likely contribute to these sex-specific propensities. The role of PTMs in heart disease is an expanding field with immense potential therapeutic targets. However, numerous PTMs remain underexplored, particularly in the context of the female heart. Estrogen, a key gonadal hormone, cardioprotective in pre-menopausal women and its loss with menopause likely contributes to disease in aging women. However, how estrogen regulates PTMs to contribute to HF development is not fully clear. This review outlines key sex differences in HF along with characterizing the contributions of novel myocardial PTMs in cardiac physiology and their regulation by estrogen. Collectively, we highlight the necessity for further investigation into women's heart health and the distinctive mechanisms distinguishing women from men.

Manipulation of mitochondrial poly(A) polymerase family proteins in Trypanosoma brucei impacts mRNA termini processing

RNA-specific nucleotidyltransferases (rNTrs) add nontemplated nucleotides to the 3′ end of RNA. Two noncanonical rNTRs that are thought to be poly(A) polymerases (PAPs) have been identified in the mitochondria of trypanosomes – KPAP1 and KPAP2. KPAP1 is the primary polymerase that adds adenines (As) to trypanosome mitochondrial mRNA 3′ tails, while KPAP2 is a non-essential putative polymerase whose role in the mitochondria is ambiguous. Here, we elucidate the effects of manipulations of KPAP1 and KPAP2 on the 5′ and 3′ termini of transcripts and their 3′ tails. Using glycerol gradients followed by immunoblotting, we present evidence that KPAP2 is found in protein complexes of up to about 1600 kDa. High-throughput sequencing of mRNA termini showed that KPAP2 overexpression subtly changes an edited transcript’s 3′ tails, though not in a way consistent with general PAP activity. Next, to identify possible roles of posttranslational modifications on KPAP1 regulation, we mutated two KPAP1 arginine methylation sites to either mimic methylation or hypomethylation. We assessed their effect on 3′ mRNA tail characteristics and found that the two mutants generally had opposing effects, though some of these were transcript-specific. We present results suggesting that while methylation increases KPAP1 substrate binding and/or initial nucleotide additions, unmethylated KPAP1is more processive. We also present a comprehensive review of UTR termini, and evidence that tail addition activity may change as mRNA editing is initiated. Together, this work furthers our understanding of the role of KPAP1 and KPAP2 on trypanosome mitochondrial mRNA 3′ tail addition, as well as provides more information on mRNA termini processing in general.

Retracted: The Role of Posttranslational Modification and Mitochondrial Quality Control in Cardiovascular Diseases.

[This retracts the article DOI: 10.1155/2021/6635836.].

Proteomics elucidating physiological and pathological functions of TDP-43.

Trans-activation response DNA binding protein of 43kDa (TDP-43) regulates a great variety of cellular processes in the nucleus and cytosol. In addition, a defined subset of neurodegenerative diseases is characterized by nuclear depletion of TDP-43 as well as cytosolic mislocalization and aggregation. To perform its diverse functions TDP-43 can associate with different ribonucleoprotein complexes. Combined with transcriptomics, MS interactome studies have unveiled associations between TDP-43 and the spliceosome machinery, polysomes and RNA granules. Moreover, the highly dynamic, low-valency interactions regulated by its low-complexity domain calls for innovative proximity labeling methodologies. In addition to protein partners, the analysis of post-translational modifications showed that they may play a role in the nucleocytoplasmic shuttling, RNA binding, liquid-liquid phase separation and protein aggregation of TDP-43. Here we review the various TDP-43 ribonucleoprotein complexes characterized so far, how they contribute to the diverse functions of TDP-43, and roles of post-translational modifications. Further understanding of the fluid dynamic properties of TDP-43 in ribonucleoprotein complexes, RNA granules, and self-assemblies will advance the understanding of RNA processing in cells and perhaps help to develop novel therapeutic approaches for TDPopathies.

SET Domain Group 703 Regulates Planthopper Resistance by Suppressing the Expression of Defense-Related Genes.

Plant defense responses against insect pests are intricately regulated by highly complex regulatory networks. Post-translational modifications (PTMs) of histones modulate the expression of genes involved in various biological processes. However, the role of PTMs in conferring insect resistance remains unclear. Through the screening of a T-DNA insertion activation-tagged mutant collection in rice, we identified the mutant planthopper susceptible 1 (phs1), which exhibits heightened expression of SET domain group 703 (SDG703). This overexpression is associated with increased susceptibility to the small brown planthopper (SBPH), an economically significant insect pest affecting rice crops. SDG703 is constitutively expressed in multiple tissues and shows substantial upregulation in response to SBPH feeding. SDG703 demonstrates the activity of histone H3K9 methyltransferase. Transcriptomic analysis revealed the downregulation of genes involved in effector-triggered immunity (ETI) and pattern-triggered immunity (PTI) in plants overexpressing SDG703. Among the downregulated genes, the overexpression of SDG703 in plants resulted in a higher level of histone H3K9 methylation compared to control plants. Collectively, these findings indicate that SDG703 suppresses the expression of defense-related genes through the promotion of histone methylation, consequently leading to reduced resistance against SBPH. The defense-related genes regulated by histone methylation present valuable targets for developing effective pest management strategies in future studies. Furthermore, our study provides novel insight into the epigenetic regulation involved in plant-insect resistance.