Nature Reviews Molecular Cell Biology最新文献

Transcription initiation in eukaryotes is a major regulatory checkpoint for ensuring that genes are precisely activated. Although the basic components of the transcription machinery were identified decades ago, recent breakthroughs in high-resolution cryo-electron microscopy have transformed our understanding of how these massive complexes function as dynamic assemblies rather than as static entities. In this Review, we focus on transcription by RNA polymerase II (Pol II) and discuss the integrated roles of the universal promoter scaffold factor TFIID, the transcription co-activator Mediator and the epigenetic status of the +1 nucleosome. We first discuss the structural basis of TFIID-mediated recognition of the core promoter and the modular assembly of the pre-initiation complex and pre-initiation complex-Mediator, which involves phosphorylation of the Pol II C-terminal domain. We then discuss how the chromatin environment regulates selection of the transcription start site and transcription directionality, before turning to the progression from transcription initiation to elongation, including promoter opening and promoter escape. Finally, we discuss transcription initiation as a programmed process, in which inhibitory factors are released and regulatory factors are progressively exchanged through competition for binding surfaces.

Microtubules are well-researched components of the cytoskeleton, yet we lack a holistic understanding that bridges molecular and cellular details with the broader functions of the microtubule cytoskeleton in development, ageing and disease. For example, how microtubule properties and functions are affected by tubulin post-translational modifications, disease-related mutations or variation of the microtubule lattice remains unexplored. In this Roadmap, we argue that integrating various experimental and theoretical approaches to bridge different spatial and temporal scales will offer new opportunities for gaining insights into essential cellular mechanisms and physiology, eventually revealing how microtubule dysfunction can lead to a broad spectrum of human diseases. Built on the current state of the art in the microtubule field, our Roadmap highlights future opportunities and challenges and proposes ways to tackle them. Given the many fundamental questions remaining to be answered, the microtubule cytoskeleton will continue to inspire scientists as it has been doing for decades.

Plants have evolved sophisticated immune systems to defend against a wide array of pathogens. These defence mechanisms are primarily mediated by cell surface pattern recognition receptors (PRRs) and intracellular nucleotide-binding leucine-rich repeat receptors (NLRs). Recent studies indicate that immune signalling involving PRRs and NLRs converges on cytosolic calcium (Ca²⁺) and other signals, which act synergistically to mount robust plant defences. However, uncontrolled activation of these defence mechanisms often negatively affects plant growth. In this Review, we discuss recent findings on the signalling mechanisms of PRRs and NLRs, including microbial recognition, receptor activation and signal transduction, as well as mechanisms that mitigate the negative impact on plant fitness associated with growth-defence trade-offs. We also discuss the interplay between the immune system and environmental stresses and explore strategies for engineering disease-resistant plants with optimized fitness.

Mitochondria are essential metabolic and signalling hubs exposed to stress, and mitochondrial damage is highly detrimental to the cell. Mitophagy - the autophagy of mitochondria - is a key mechanism that maintains both mitochondrial integrity and metabolic flexibility. Mitophagy occurs via multiple pathways that either involve activation of PTEN-induced kinase 1 (PINK1) and the E3 ubiquitin-protein ligase Parkin, or are independent of PINK1 and Parkin. Recessive mutations in PINK1 and PKRN (the gene that encodes Parkin) cause early-onset Parkinson's disease and have provided key mechanistic insights into mitophagy. However, emerging findings indicate that mitophagy is also executed by other molecular routes. Despite these molecular advances in mitophagy characterization, the physiological roles of these pathways in mammals and the specific contexts or conditions in which they operate remain poorly defined. This Review summarizes current understanding of PINK1-Parkin-dependent and independent mitophagy pathways, highlighting mechanistic distinctions and coordinated regulation. We also examine physiological and pathological triggers of mitophagy, as well as the expanding therapeutic potential of targeting mitophagy in disease.