搜索结果：Trends in biochemical sciences

RNA imprinting refers to the co-transcriptional binding of (a) factor(s) that remain associated with the RNA as it enters the cytoplasm, where it/they regulate(s) post-transcriptional processes. Transcription factors (TFs), such as yeast Sfp1 and mammalian tristetraprolin, FUS, and Yin-Yang 1, exemplify RNA imprinting by zinc-binding proteins. These TFs contain large intrinsically disordered regions (IDRs) and have the capacity to bind both DNA and RNA. The most prevalent zinc-binding domains among TFs are zinc fingers (ZFs), which recognize nucleic acids through modular tandem arrangements. We hypothesize that the structural organization of ZFs enables switching between DNA and RNA during transcription. The IDRs of these TFs, together with the nascent RNA, contribute to transcription-related biomolecular condensates that may facilitate this switching, enabling their imprinting.

PINK1/Parkin-mediated mitophagy and other related mitochondrial quality control pathways are critical to maintaining cellular homeostasis and neuronal health, and indeed, mutations in PINK1 and PRKN that disrupt this pathway cause early-onset Parkinson's disease. While PINK1-dependent Parkin recruitment to damaged mitochondria has been established for over a decade, recent structural and biochemical advances have illuminated the mechanisms governing their allosteric activation and integration into broader cellular signaling networks. This review synthesizes these insights, focusing on the molecular determinants of PINK1/Parkin activation and the regulatory crosstalk that integrates mitophagy with other cellular stress responses. These mechanistic advances position the PINK1/Parkin pathway as a promising, tractable therapeutic target for Parkinson's disease and related pathologies.

Single-cell proteomics (SCP) has emerged as a transformative approach for characterizing cellular heterogeneity at the protein level. Recent advances in mass spectrometry workflows, with improvements spanning sample preparation, peptide separation, data acquisition, and data interpretation, have enabled unprecedented proteome depth and throughput at single-cell resolution. Beyond technological innovations, SCP is now addressing complex biological questions in oncology, developmental biology, and neuroscience, revealing dynamic cellular states and regulatory mechanisms. Integration with other single-cell omics is bridging the gap between genotype-phenotype relationships and uncovering multilayered regulation. In this review, we summarize recent progress in SCP technologies and highlight emerging applications and integrative strategies that mark a transition from technological development to broad biological understanding.

Transcriptional responses are initiated immediately after the recognition of pathogen-associated molecular patterns by pattern recognition receptors, enabling host cells to deal with inflammatory stimuli, including microbial infections. In turn, these inflammatory transcriptional programs must be tightly controlled to prevent potential detrimental consequences, such as immunopathological or even fatal outcomes. To date, many well-defined mechanisms have been reported that contribute to the transcriptional control of inflammatory gene expression at multiple levels. Here, I mainly focus on reviewing recent progress in post-translational modifications, in particular, how the ubiquitination-deubiquitination cycle controls inflammatory gene transcription mediated by nuclear factor kappa-light-chain-enhancer of activated B cells and interferon signaling pathways. Lastly, I will emphasize the importance of understanding gene-specific mechanisms in controlling inflammatory gene transcription.

Understanding how the spliceosome integrates regulatory cues to generate RNA diversity remains a central question in gene expression control. Emerging evidence reveals a multilayered framework in which splicing is governed by nuclear architecture and the physical state of nuclear speckles. These condensates function as phosphorylation-sensitive hubs that concentrate splicing machinery and couple signaling pathways to RNA processing. Chromatin organization, transcript architecture, and condensate properties are tightly coordinated, adding spatial constraints to spliceosome function. Recent findings further uncover temporal regulation through cell cycle and ultradian dynamics of speckle assembly. In this review, we synthesize these advances and propose a unified model in which charge-dependent phosphorylation of splicing factors drives condensate remodeling, linking nuclear organization to regulated splicing outcomes across space and time.

The site-specific incorporation of noncanonical amino acids (ncAAs) has revolutionized protein research. However, synthesizing multifunctional biopolymers demands moving beyond single-type ncAA incorporation to simultaneously encoding multiple distinct ncAAs. This review summarizes transformative progress in the genetic encoding of multiple distinct ncAAs, including the development of mutually orthogonal translation systems and the expansion of codon repertoires. We highlight recent breakthroughs that have achieved the incorporation of multiple distinct ncAAs. Notably, integrating rare codon recoding with stop codon suppression in mammalian systems has recently enabled the genetic encoding of five distinct ncAAs. These innovations establish a robust platform for advanced biosensors, next-generation therapeutics, and synthetic biology with expanded chemical repertoires.

Extracellular adenosine (e-Ado) is a critical signaling molecule, yet its origin beyond energy stress and inflammation is underexplored. Herein, we propose that Ado is ubiquitously generated in the S-adenosylmethionine transmethylation pathway and integrate this source with the concept of cellular privilege in nutrient acquisition. In this model, less privileged cells convert Ado to adenosine monophosphate (AMP) under nutrient scarcity, activating AMP-activated protein kinase, while privileged cells release Ado to signal for resources. We define Ado as a sensor of the balance between cellular activity, reflected in methylation, and nutrient supply, reflected in ATP recycling. This framework redefines Ado's role in immunity, brain function, and aging and highlights transmethylation-derived Ado as a key factor in the tumor microenvironment and immunotherapeutic strategies.

Glutamine is the most abundant circulating amino acid and a central nutrient supporting carbon and nitrogen metabolism. It donates nitrogen for nucleotide and amino acid biosynthesis, protein glycosylation, and provides carbon for the tricarboxylic acid cycle anaplerosis. Glutamine catabolism maintains redox homeostasis via glutathione production, as well as the synthesis of polyamines, urea cycle precursors, and neurotransmitters. Glutamine residues in proteins serve as sites for post-translational modification, while de novo glutamine synthesis is essential for ammonia detoxification. Although glutamine metabolism is regulated by mass action and product inhibition, emerging evidence reveals additional post-translational mechanisms, including regulation through higher-order structural assemblies of enzymes. In this review, we highlight the multifaceted roles of glutamine and emphasize emerging regulatory mechanisms that govern glutamine metabolism.

Interpreting variants of uncertain significance remains a central challenge in human genomics. Base and prime editors have launched a new era of precision functional genomics, enabling programmable, double-strand break-free introduction of point mutations and small indels directly within the genome. Here, we review the technological evolution of these editors and their transformative application in high-throughput functional screens. We highlight how base and prime editing platforms systematically annotate clinical variants, reveal mechanisms of drug resistance and immune evasion, and dissect fundamental biological processes at single-nucleotide resolution. Crucially, we address current challenges and future perspectives for precision editing screens. By enabling causal genotype-to-phenotype mapping, precision editing screens are redefining genomic variation interpretation and accelerating its translation into precision diagnostics and therapeutics.

Precise regulation of protein abundance is essential for cellular function and physiology. Conventional approaches are often limited by insufficient resolution or unintended crosstalk. In contrast, orthogonal control technologies enable programmable and precise modulation of protein abundance while remaining insulated from native networks. In this review, we summarize the development and application of regulation technologies with different orthogonality across multiple levels. Orthogonal transcriptional control primarily involves the design and engineering of orthogonal RNA polymerases and transcription factors; orthogonal translational regulation focuses on advances in genetic codon expansion and post-translational modifications; targeted protein degradation and compartmentalized regulation are also discussed. Finally, we highlight the integration across the different levels described above. This review might bring disruptive insights and conceptual breakthroughs to precision medicine and sustainable biomanufacturing.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor, prominently expressed in barrier tissues and organs. The functional diversity of AHR signaling in physiology stems primarily from ligand specificity and crosstalk with its protein partners. Its ability to sense chemically diverse cues underpins its emerging therapeutic potential in autoimmune and oncological disorders. Recent breakthroughs in structural biology have elucidated key aspects of AHR function and modulation, including its promiscuous ligand recognition, heterodimerization, DNA response element engagement, and ligand-dependent receptor activation, distinguishing it from other basic helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) family members. In this review article, we discuss these advances, highlighting how high-resolution structural insights are redefining our mechanistic understanding of AHR and guiding strategies for its pharmacological modulation across diverse physiological and pathological contexts.

Glycans are polymeric carbohydrate chains that often decorate proteins and lipids present on cell surfaces and in the extracellular space, thereby influencing cell interactions, immune responses, and host-microbiome relationships. Glycans are highly dynamic and can undergo a plethora of post-synthetic modifications, including O-acetylation, sulfation, and sulfamation. In this review, we examine how these glycan modifications are established and how they influence human health, from cell signaling to host-pathogen dynamics. We propose terming these glycan modifications, which give rise to a greater diversity of glycans, collectively as the epiglycome. Despite their biological importance, glycan modifications are considerably less well studied than the underlying glycans and proteins. However, advances in chemical and biochemical tools are enabling greater insights into their roles and translational potential.

Post-translational modifications (PTMs) are emerging as crucial regulators of proline metabolism, a pathway central to redox homeostasis, stress adaptation, and disease progression conserved across species. Beyond transcriptional regulation, PTMs such as phosphorylation, acetylation, and ubiquitination fine-tune the activity, stability, and localization of proline metabolic enzymes, including those involved in its biosynthesis and catabolism. Advances in proteomics and structural biology now provide insights into how these reversible modifications modulate enzyme oligomerization and metabolic flux, with involvement in plant stress tolerance and cancer cell survival. Here, we synthesize recent observations across kingdoms, discuss how PTMs integrate into metabolic control, and highlight future directions for exploiting PTM-based regulation in agriculture and human health.

N6-methyladenosine (m6A) extends beyond mRNAs to modify diverse noncoding RNAs (ncRNAs), including long ncRNAs, circular RNAs, and miRNAs. Through stage-specific regulation, m6A orchestrates ncRNA biogenesis by modulating processing, stability, localization, and translation. At higher regulatory levels, m6A fine-tunes ncRNA functions across molecular and structural hierarchies by reshaping RNA-RNA and RNA-protein interactions that influence gene expression. Conversely, ncRNAs impose multilayered feedback on m6A writers, erasers, and readers, forming reciprocal loops that couple chromatin regulation with RNA metabolism. These hierarchical circuits constitute an epitranscriptomic layer that coordinates transcriptional and posttranscriptional control. We further outline conserved yet lineage-specific m6A-ncRNA networks across animals and plants, illustrating how this dynamic system integrates chemical marks with gene regulatory complexity across kingdoms.

Multispecificity involves high-affinity binding to multiple related ligands while preserving discrimination against other ligands. The binding of tick evasins to human CC chemokines exemplifies key principles of multispecific binding: a rigid core recognising conserved features of all targets, with flexible peripheral regions enabling discrimination within the target family.

Extracellular acidification is a defining feature of many pathological microenvironments and is sensed by G protein-coupled receptors (GPCRs)-GPR4, GPR65, and GPR68. These proton-sensing receptors regulate vascular, immune, and neural responses and are increasingly implicated in inflammation, cancer, fibrosis, and ischemic injury. Recent cryo-electron microscopy structures have revealed the molecular basis of proton detection, highlighting dynamic extracellular loop rearrangements, pH-sensitive histidine networks, and a stepwise activation mechanism that tunes G protein coupling and signaling bias. Emerging structural evidence also shows lipid modulation and species-specific adaptations that shape receptor responsiveness. These advances provide a structural and mechanistic framework for developing selective modulators of proton-sensing GPCRs as therapeutic targets in acidic disease environments.

Adenosine Monophosphate (AMP)-activated protein kinase (AMPK) is a critical kinase in the control of cellular metabolism, and in recent years, accumulating evidence has demonstrated that AMPK plays a critical role in the regulation of various types of regulated cell death (RCD) pathways, including apoptosis, necroptosis, pyroptosis, and ferroptosis. In this review, we will first discuss the regulatory roles of AMPK in these forms of RCD. Then, we will examine the implications of AMPK in diseases such as cancer, diabetes complications, ischemia-reperfusion injury, and infectious diseases, focusing on the therapeutic potential of AMPK activators and inhibitors through the regulation of different types of RCD.

Enzymes play critical roles in all aspects of biology, making them important targets for therapeutics in infectious diseases and cancer. In addition to the well-known and exploited competitive and suicide inhibitors, reaction hijacking compounds are emerging as important inhibitors with therapeutic potential. We review how hijacking inhibitors exploit the enzyme's catalytic cycle to generate potent modulators in situ. The target enzyme catalyses the formation of a covalent adduct between a substrate-mimicking hijacker and a co-substrate or cofactor. Susceptible enzymes include members of the superfamily of adenylate-forming enzymes, NAD+-metabolising enzymes, and a range of cofactor-dependent enzymes. Hijacking compounds are usually unreactive until activated by the target enzyme, affording good selectivity and potency, as well as favourable physiochemical properties and synthetic tractability.

Cell fate is shaped by external cues and intrinsic cellular states. While supracellular signals, such as growth factors, provide instructive guidance, emerging evidence highlights the role of cell-autonomous properties in modulating these responses. Among these, lipid membrane composition, especially glycosphingolipids (GSLs), has gained attention as a contributor to cellular identity. GSL biophysical properties guide the formation of membrane nanodomains, which serve as platforms for receptor signaling and protein sorting, while their structural heterogeneity enables distinct interactions with signaling molecules and recognition factors. In this review, we discuss the biosynthesis and organization of GSLs, their biological roles, and emerging technologies for their analysis. Together, these studies support the view that GSLs contribute to cell-type-specific membrane properties and help shape cellular states and identity.