Essays in biochemistry最新文献

Through its various roles in protein quality control, membrane dynamics, and cellular survival pathways, the AAA+ ATPase p97/valosin-containing protein emerges as a significant regulator of mitochondrial homeosta sis. This review comprehensively examines the multifaceted functions of p97 in mitochondrial biology, spanning from mitochondria-associated degradation to newly discovered functions in organellar cross-talk and disease pathogenesis. Underlying its cellular importance, p97 mutations are found in amyotrophic lateral sclerosis and frontotemporal dementia. To elucidate its mechanistic contribution to these processes, we provide a detailed table (Table 1) listing all known mitochondrial Cdc48/p97 substrates and associ ated proteins, categorized by their respective pathways. Recruitment to most of these substrates occurs by specialized adaptors, including Doa1/phospholipase A-2-activating protein, UBXD8, and UBXN1. p97 orchestrates the extraction and proteasomal degradation of outer mitochondrial membrane proteins, which are essential for maintaining mitochondrial integrity. For example, by controlling the turnover of fusion factors MFN1/2 and fission machinery, p97 regulates mitochondrial dynamics. p97 also governs apoptotic signaling through the regulated degradation of anti-apoptotic factors, such as myeloid cell leukemia-1 and VDAC, thereby modulating mitochondrial permeability. In mitophagy, p97 enables the clearance of damaged organelles by extracting ubiquitinated substrates and recruiting autophagy machinery. Beyond proteolysis, p97 facilitates recycling of endoplasmic reticulum-mitochondria contact sites through regulation of UBXD8-dependent lipid metabolism. Recent discoveries have revealed p97's involvement in pathogen host interactions and circular RNA-mediated regulation, thereby expanding our understanding of its cellular functions. The emerging picture positions p97 as an integrative hub co-ordinating mitochondrial protein homeostasis, organellar dynamics, and cell fate decisions, with therapeutic potential for metabolic and neurodegenerative disorders.

SUMOylation, a protein post-translational modification (PTM) involving the covalent attachment of small ubiquitin-like modifier (SUMO), regulates a wide range of cellular processes. The key hallmark of SUMO that distinguishes it from ubiquitin is the hydrophobic groove that binds short linear motifs known as SUMO-interacting motifs (SIMs), which are found across a broad spectrum of partners, including SUMO E3 ligases and downstream effector proteins such as transcription factors, DNA-repair proteins, ubiquitin E3 ligases and cell-signalling components. In addition, various effectors interacting in a SIM-independent manner have been reported. In this review, we summarise the current understanding of non-covalent SUMO interactions mediated by SIMs and other, alternative SUMO-binding elements. Focusing on the evolution and structural basis of these interactions, we discuss the methodological approaches used in the field, outline emerging mechanisms and concepts and highlight key open questions.

Protein quality control (PQC) systems are crucial for maintaining cellular proteostasis, particularly under stress that promotes misfolded protein accumulation. A central component of this response is the assembly of stress granules (SGs), cytoplasmic condensates of RNA and proteins that temporarily stall translation. Aberrant SG dynamics, often linked to mutations in SG proteins, contribute to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), where persistent protein aggregates are hallmarks. This review examines the emerging role of the ubiquitin-like modifier NEDD8 and its deconjugating enzyme NEDP1 in regulating SG homeostasis. Recent studies identify NEDP1 as a critical factor controlling SG clearance. Inhibition of NEDP1 enhances SG turnover, prevents pathological solidification, and promotes the disassembly of toxic aggregates through hyper-NEDDylation of PARP1, a DNA repair enzyme that also governs SG dynamics. Unlike broad-spectrum PARP1 inhibitors, which can impair DNA repair and cause cytotoxicity, NEDP1 inhibition offers a stress-specific approach that preserves normal cellular functions. Encouragingly, NEDP1 inhibition effectively causes aggregate elimination in ALS patient-derived fibroblasts and restores motility in Caenorhabditis elegans disease models. Altogether, these findings highlight NEDP1 as a key regulator of SG regulation and a promising therapeutic target for ALS and related neurodegenerative disorders.

The endosomal sorting complex required for transport (ESCRT) is a conserved molecular machinery that plays fundamental roles in the cellular endomembrane network. Functioning as a core mechanism, ESCRTs recognize and sort ubiquitinated membrane proteins, which are subsequently sequestered into vacuoles (lysosomes in other eukaryotes) for degradation by luminal proteases or recycled from endomembranes to the plasma membrane for functional reuse. Through these processes, the ESCRT machinery acts as a critical regulator of plant development and stress adaptation. Recent studies on plant ESCRT components, particularly VPS23A and FREE1, have identified their key roles in abiotic stress responses, with a focus on their modulation of abscisic acid (ABA) signaling pathways. Additionally, post-translational modifications including ubiquitination and phosphorylation have been shown to play pivotal roles in these regulatory processes. Notably, FREE1 has been identified to mediate endosome membrane bending and scission independently of the ESCRT machinery, a mechanism crucial for plant responses to osmotic stress. This review summarizes and discusses recent advances in ESCRT-mediated signaling in plant abiotic stress responses, aiming to highlight the fundamental roles of ESCRTs in plant biology and provide key targets for molecular breeding of abiotic stress-tolerant crops.

Cancer metastasis is one of the hallmarks of cancer. This multistep process involves a cascade of alterations at the cellular and molecular level, including the epithelial-to-mesenchymal transition (EMT), invasion, migration, extracellular matrix (ECM) degradation, angiogenesis, and colonization. Expression level of critical factors associated with these processes is altered at the post-translational level through ubiquitination. Therefore, E3 ubiquitin ligases, components of the ubiquitin-mediated proteasome system, play a crucial role in controlling each step of metastasis by promoting the ubiquitination of several important factors. In this review, we have summarized the importance of E3 ligase in metastasis. Several E3 ligases act as promoters, while others act as repressors of metastasis. This article focuses on the potential role of E3 ubiquitin ligases in cancer metastasis and reveals their molecular function and targets, which are crucial for therapeutic interventions in anti-cancer therapies. Further, we covered the development of small molecule inhibitors and proteolysis-targeting chimeras to target E3 ubiquitin ligases involved in promoting metastasis for therapeutic intervention. Despite tremendous advancements, there are still many unanswered questions, especially regarding the complete characterization of the diverse range of E3 ligase functions and the conversion of preclinical discoveries into successful clinical treatments. In addition, future directions are concentrated on using technologies to develop highly specific therapeutic interventions and exploring their potential in combination with other treatment modalities, including immunotherapy, to ultimately overcome the challenges of cancer metastasis.

R-loop, a three-stranded nucleic acid structure consisting of the RNA:DNA hybrid and the displaced singlestranded DNA, is crucial for many cellular processes but could be a threat to genome integrity if dysregulated. The homeostasis of R-loops is governed by various factors including helicases, nucleases, and chromatin remodelers. Since there are many excellent reviews about R-loops, we focus on discussing how R-loop homeostasis is regulated via nucleic acid and protein modifications. We summarize how RNA modifications such as N6-methyladenosine (m6A), N5-methylcytosine (m5C), and potentially 3-methylcytidine (m3C), alongside DNA modifications such as deamination, methylation, and oxidation, influence R-loop dynamics. Moreover, we discuss how protein modifications, including ubiquitination, SUMOylation, acetylation, methylation, and phosphorylation, modulate the activity, stability, or recruitment of R-loop processing factors. Importantly, these modifications often interact with each other and exhibit context-dependent roles, either promoting R-loop formation or facilitating resolution. Elucidating how these chemical codes orchestrate R-loop homeostasis will facilitate our understanding of the mechanisms governing R-loop homeostasis and could provide some insights into genome maintenance, gene expression, and pathogenesis caused by R-loop dysregulation.

The aberrant accumulation of misfolded proteins marked by cellular dysfunction and progressive neuronal loss is the hallmark of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. This review examines the pivotal role of ubiquitin modifications in altering the fate of aggregation-prone proteins such as tau, α-synuclein, mutant huntingtin, TAR DNA-binding protein 43 and superoxide dismutase 1. The ubiquitin signatures identified by their linkage types, chain architectures and site specificities emerge as a complex regulatory language that influences the clearance, aggregation or cellular propagation of these aggregating proteins. The dysregulation of other components of the ubiquitin association pathways, such as impaired E3 ligases and deubiquitinases, also contributes to the inefficient protein disposal and disease progression. Understanding how ubiquitin signatures alter the spatiotemporal dynamics of aggregating proteins is critical for advancing our knowledge of disease biology. Here, we focus on the role of ubiquitin modifications and their associated regulators affecting protein fate and neurotoxicity, and highlight the current therapeutic strategies targeting the degradation of aggregating proteins to uncover potential avenues for treating neurodegenerative diseases.

Ubiquitination is a fundamental post-translational modification essential for nearly all cellular activities. Traditionally, ubiquitination has been understood as a protein modification, where ubiquitin (Ub) molecules are covalently attached to the lysine residues of substrate proteins, thereby modulating their function, localization, or degradation. However, recent discoveries have expanded the scope of ubiquitination beyond protein substrates. One of the examples is ubiquitination of ADP-ribose moieties on proteins or nucleic acids that leads to the formation of a dual-hybrid modification ADP-ribose-Ub (ADPr-Ub). This novel form of ubiquitination is catalyzed by Deltex ubiquitin ligases that act in concert with PARPs (Poly (ADP-ribose) polymerases), enzymes modifying their substrates by ADPr modification. This review summarizes our current knowledge of mechanisms and potential functional implications of ADPr-Ub. We also cover other examples of the interplay between ADP-ribosylation (ADPr) and ubiquitination beyond Deltex enzymes and ADPr-Ub.

More than 80% of intracellular proteins are degraded by the ubiquitin-proteasome system. This system relies on a cascade of enzymes-E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3 (ubiquitin ligase)-to catalyze the polyubiquitination of target proteins, which are then recognized and degraded by the 26S proteasome. Among these enzymes, E3 ubiquitin ligases play a central role by specifically recognizing degron motifs on substrate proteins. The presence and accessibility of these degrons often dictate the half-life and stability of a given protein. Leveraging this mechanism, the artificial introduction of degrons or degron mimetics into otherwise stable proteins has emerged as a novel strategy in drug discovery for selectively degrading disease-causing proteins. In this short review, I will highlight small-molecule degron mimetics that have been developed for targeted protein degradation.

The 26S proteasome is a multi-subunit protease complex that degrades most eukaryotic cellular proteins. It not only regulates individual protein's half-lives but also maintains proteome homeostasis and modulates immunological responses. During conditions involving large-scale proteome remodeling, such as fibrosis and cellular differentiation, the 26S proteasome plays a central role in the rapid removal of excess cytosolic proteins. However, the precise mechanisms underlying this process remain unclear. In this review, we highlight the significance of the immunoproteasome, a specialized variant of the proteasome composed of alternative catalytic subunits, in fibrosis of the kidney, lung, heart, and liver. Immunoproteasomes broaden the antigen repertoire by producing distinct peptide fragments that are preferentially presented to specific immune cell populations. They can also proteolyze substrates with certain ubiquitin (Ub) chain linkages or even those lacking Ub tags. We propose that the immunoproteasome functions as a highly specialized protease in fibrotic tissues, contributing to the transition from a complex but homeostatic proteome to a simple fibrotic proteome.