Modulation of host actin dynamics by pathogens to enter and survive inside cells is a central theme of many pathogenic infections. Decades of research have given us deep insights into the role of individual pathogenic factors in regulating host actin dynamics. However, the combinatorial effects of pathogenic factors and their complex interplay in generating the wide plethora of actin structures are just beginning to be unraveled. This review aims to provide an emergent perspective on the modulation of host actin dynamics by pathogens. We begin with a discussion of pathogen-generated actin structures, provide insights into molecular mimicry mechanisms used by pathogenic factors to regulate actin remodeling, and conclude by examining the effect of pathogenic infections on modulation of host actin dynamics.
Chemoattractant gradients guide cell migration in immunity, tissue repair, and development, yet their spatial and temporal distribution remains difficult to measure. In this review, we discuss how the field is moving beyond static source maps and indirect cellular proxies toward direct visualization of extracellular guidance cues. We outline the strengths and limitations of classical approaches for inferring chemoattractant gradients and highlight new strategies provided by genetically encoded chemoattractant indicators (GECHIs). Emerging PBP- and GPCR-based biosensors enable continuous visualization and localization of extracellular ligands in living tissues using fluorescence intensity- or lifetime-based readouts. Although the current toolbox is limited to a small number of chemoattractants, ongoing sensor development is likely to expand ligand coverage and enable multiplexed measurements with spectrally distinct sensors in the near future.
Within the family of protein kinases there is a subgroup of 'evolutionarily related members of the total human kinome' that are devoid (or have very limited) enzymatic activity. These proteins, so-called pseudokinases, play important functions thanks to their capacity to establish regulatory protein-protein interactions. Specifically, this opinion article focuses on a group of pseudokinases called Tribbles. Tribbles (Trbl) was originally discovered in Drosophila, followed by the subsequent identification of their orthologs in mammals (TRIB1, TRIB2, TRIB3, and STK40). Work over the last decades has shown how these proteins contribute to fine-tuning key signaling pathways involved in the regulation of proliferation, differentiation, inflammation and adaptation to nutritional changes. Accordingly, dysregulation of Tribbles proteins (TRIBs) contributes to the establishment and progression of insulin resistance, obesity, type II diabetes, atherosclerosis and cancer. Here, we will discuss some of the mechanisms by which Tribbles pseudokinases carry out their functions and the crucial importance of cell context in defining the precise role played by each of the TRIBs, with emphasis on TRIB1 and TRIB3, under different physiopathological situations.
Primary cilia are sensory organelles that host various signalling receptors and proteins to coordinate signalling pathways essential for tissue homeostasis. This review explores the molecular mechanisms by which intraflagellar transport (IFT) machinery, the BBSome coat complex, small GTPases, and various secondary messenger signalling molecules cooperate to establish and maintain ciliary composition. We discuss how IFT trains, guided by kinesin-2 and dynein-2 motors, traffic receptors and signalling components into and out of the cilium, and how the lipid composition within the cilium plays a regulatory function. We also described how secondary messengers such as cAMP and Ca2+ coordinate ciliary signalling outputs, including hedgehog and insulin secretion. Finally, we have also discussed how the BBSome selects cargo for export and the role of small GTPases in its trafficking, together ensuring the compositional integrity and signalling fidelity of this organelle. A mechanistic understanding of these integrated trafficking and signalling systems provides a framework for elucidating the pathogenesis of ciliopathies and identifying potential therapeutic targets.
Eukaryotic cells rely on long-range microtubule transport to accurately position mitochondria, and other organelles and vesicles with spatial and temporal precision. While kinesin and dynein motors drive directional movement, motor activity alone cannot explain the diversity and adaptability of organelle trafficking in vivo. Here, we synthesize recent evidence that non-motor microtubule-associated proteins (MAPs) convert microtubules into information-rich transport networks by decorating specific lattice subsets, modifying microtubule mechanics and controlling motor access and activation. Through steric filtering, modulation, or activation, MAPs impose motor-specific rules that shape transport efficiency and directionality. MAPs also couple trafficking to signaling by interacting with kinases, phosphatases, and receptors, and their dysregulation contributes to neurodegeneration and cancer, highlighting MAP-regulated transport as a therapeutic target.
Effective immune surveillance and host defense require leukocytes to patrol their environment and rapidly respond to threats. Traditionally, immune cells detect inflammatory or pathogenic cues that guide them to sites of infection or tissue damage. In doing so, they navigate across tissues that differ widely in physical and mechanical properties, which can change with physiological or pathological states. Beyond biochemical cues, immune cells actively sense and integrate these mechanical signals, translating them into responses that regulate their migration and immune functions. This review summarizes recent findings in immune cell mechanosensing, from membrane mechanosensors to cytoskeletal and nuclear mechanotransduction, highlighting how these pathways control immune cell migration. We further discuss the role of mechanical cues in shaping the immune-surveillance properties of immune cells, a direction we believe the field is moving toward.
Cells in tissues often navigate complex environments, encountering physical obstacles which impose mechanical confinement. The nucleus -the largest organelle of the eukaryotic cell-is emerging as a key platform for integrating mechanical signals from the extracellular environment. A mechanically stiff nucleus often limits migration through confinement. It is becoming increasingly clear that the nucleus does not passively resist forces. Subnuclear organisation can change upon mechanical stress, revealing an impressive capability for adaptation to environmental challenges that underpins cell function, developmental potential and can support invasion and migration both in physiology and disease.
Cell migration is a fundamental biological process essential for development, tissue repair, and cancer metastasis. While cytoskeletal dynamics, adhesion turnover, and biochemical signalling are known regulators of migration, intracellular organelles have traditionally been regarded as passive components. Emerging evidence now reveals that organelles actively reorganize and polarize during migration, undergoing spatial and functional specialization to coordinate force generation, adhesion dynamics, metabolic support, and mechanochemical signalling. In this review, we discuss recent advances highlighting how endo-lysosomes, the endoplasmic reticulum (ER), mitochondria, the Golgi apparatus, and migrasomes regulate cell migration. We synthesize emerging principles, identify common mechanistic themes, and outline key open questions that will guide future investigations into how organelles govern cell motility across physiological and pathological contexts.
Tissue repair is a dynamic, multicellular response that relies on the precise spatiotemporal coordination of diverse cell types. Here, we discuss how recent advances have accelerated our mechanistic understanding of these collective cellular behaviours, particularly in epithelial barrier tissues like the skin. We highlight studies unravelling the intricate crosstalk that patterns cell behaviours across the repairing tissue and how vulnerable cells are endowed with striking stress resilience and memory. The integration of cutting-edge live imaging, single-cell profiling and computational approaches are now revealing the complexities of effective and pathological repair at an unprecedented resolution, opening new avenues for therapeutic intervention.
The cell plasma membrane of eukaryotic cells is a fantastically complex and important system ensuring the transport of information from the environment towards individual cells and vice versa. It provides a mechanical and chemical delimitation of the cell, enabling cell migration, the formation of tissues, as well as the transport of electrical signals. The watchmaker's approach of understanding this complex system by rebuilding aspects of it in minimal systems using purified and reconstituted proteins has proven to be very powerful and has delivered crucial insights into key mechanisms governing cell membrane activities and organisation. However, recent advances have been limited, and it remains to be seen whether functional mimics of the cell surface can be engineered and what advantage those would deliver compared to more traditional methods of synthetic biology. This piece summarises some of the recent advances and gives a perspective on where the field could go.
Isoform generation is a strategy for fine-tuning the activity of essential proteins, particularly during cell differentiation and cancer development. The coding sequence of mRNA is determined by alternative splicing during pre-mRNA processing, allowing the generation of different mRNA variants from a single gene. Alternative splicing is modulated by several pathways, including the selection of transcription initiation and termination sites. The activity of RNA-binding proteins involved in splicing is affected by spatial factors, including RNA folding, separation in local bio-condensates, and the three-dimensional organization of chromatin. The length of untranslated regions and the selection of alternative polyadenylation sites impact mRNA stability and translation accessibility, ultimately controlling the abundance of specific isoforms. This review highlights recent discoveries about the nuclear factors that modify alternative splicing, thereby coordinating the variety of mRNA and protein isoforms with cell state.
mTORC1 is a central regulator of cell growth and metabolism, classically viewed as a binary switch that promotes anabolic programs while suppressing catabolic pathways. Recent work advances this simplified model by revealing that mTORC1 signaling is highly substrate-specific, with distinct classes of substrates differentially regulated according to their modes of recruitment and subcellular localization. In this review, we discuss emerging evidence demonstrating that mTORC1 activity and its lysosomal localization can be functionally uncoupled, enabling selective phosphorylation of lysosomal versus non-lysosomal targets. We highlight how upstream regulatory pathways and post-translational modifications shape these substrate-specific outputs, and consider the implications of downstream uncoupling for the fundamental understanding of mTORC1 biology as well as human health and disease.
Intracellular lipid storage is mediated by lipid droplets. Once considered inert lipid inclusions, these structures are now recognized as ubiquitous, multifunctional organelles at the core of cell biological control of metabolism. Lipid droplet dysfunctions are linked to a range of metabolic diseases including obesity, diabetes, steatohepatitis, and lipodystrophy. Intriguingly, not all lipid droplets are the same. Striking structural and functional differences are regularly observed between the lipid droplets of different tissues and cell types, and even within the lipid droplet pool of a single cell. Here, we discuss the current views on the molecular mechanisms that create and maintain this high degree of lipid droplet heterogeneity.
Signal packaging is a fundamental mechanism that enables cells to manufacture, target, stabilize, and amplify chemical cues. By organizing chemokines, lipid mediators, and guidance factors into glycan lattices, lipid-protein carriers, membrane nanodomains, extracellular vesicles, and other structures, cells transform intrinsically labile chemical cues into long-lived, interpretable instructions. Such packaging maintains gradients in crowded tissues and ensures timely delivery to targeted recipients, thus transforming chemical signals into actively orchestrated and effective programs. Failures in this system contribute to metastasis, chronic inflammation, and barrier dysfunction. In this review, we highlight compartmentalized signal packaging as an evolutionary design principle for cellular communication and discuss how recognizing this information layer provides new insights into the control, engineering, and dysregulation of cellular guidance systems.
Lipids are now recognized as central regulators of cellular signaling, extending well beyond their traditional roles in membrane structure and energy storage. As spatially confined and rapidly inducible messengers, signaling lipids integrate membrane dynamics, metabolism, and signal transduction to control processes like inflammation, immune responses, vesicular trafficking, cytoskeletal organization, and cell fate decisions. This review highlights key mechanistic principles underlying lipid signaling specificity, including localized biosynthesis, enzymatic turnover, and receptor engagement. We trace the evolution of the field from classical eicosanoids and phosphoinositides to sphingolipids, lysophospholipids, and endocannabinoids, and focus on emerging mediators such as fatty acid esters of hydroxy fatty acids, specialized pro-resolving mediators, and lysophosphatidylserines. We conclude by discussing how dysregulated lipid signaling contributes to disease and outline future directions, emphasizing membrane contact sites, signaling crosstalk, and advances in lipidomics and imaging.
Autophagy is initiated by the formation of a double-membrane autophagosome which is fine-tuned by the involvement of multiple protein machineries, organelles, and membrane pools. Autophagosome formation proceeds through steps requiring membrane nucleation, membrane expansion, and vesicle closure, initiated and coordinated by the cohort of ATG (Autophagy) proteins and lipids, such as PI(3)P and PE. Recent studies provide insights into how different molecular machineries act and interact to enable this complex vesicular pathway. Here, we review the current understanding of the steps that lead to autophagosome formation from a molecular perspective and, in this context, discuss the role of protein-membrane crosstalk in moulding the phagophore structure.
Myeloid immune cells play crucial roles in tissue homeostasis, wounding, inflammation, infection, and allergic reactions. Individual myeloid cell types have evolved unique dynamics adapted to their specific functions in the tissues, ranging from long-term residency to rapid migration. The interplay between actin network expansion and contraction underlies the movement of all myeloid cells, but distinct cell types utilize receptor-mediated adhesion differently when interacting with their environment. This results in cell-type specific morphologies and motility behaviors, from fast amoeboid locomotion to slow mesenchymal-like motility. We provide an overview of the migration modes employed by neutrophils, monocytes, macrophages, dendritic cells, and mast cells, highlighting the wide spectrum of migration strategies within the myeloid compartment.
Lipid metabolism and storage are highly compartmentalized processes. Key organelles defined to govern lipid synthesis (ER), storage (lipid droplets, LDs), and catabolism (mitochondria) work in synchrony to coordinate lipid metabolic flux. Interactions between these organelles play important roles in metabolite exchange and signaling that vary in response to physiological conditions. Alterations in organelle crosstalk or imbalances between anabolic and catabolic pathways are commonly observed in diseased states, including metabolic dysfunction-associated steatotic liver disease (MASLD). While many studies have characterized two-organelle interactions (e.g., LD mitochondria), there is a general lack of consideration of how the presence of other organelles impacts the function of these contacts. This review aims to provide a concise summary of the regulation, function, and complexity of how these organelle interactions compartmentalize hepatic lipid metabolism.
Infectious pathogens must adapt to the metabolic landscapes of their hosts, often exploiting host-derived nutrients while mitigating the stresses these resources impose. Among these challenges, host lipids are both a rich energy source and a potential liability, requiring tight regulation during infection. Mycobacterium tuberculosis, the causative agent of tuberculosis and the leading cause of death from a single infectious agent, exemplifies an extreme adaptation to lipid-rich environments. Recent studies have uncovered coordinated host and bacterial pathways that mediate fatty acid transfer, uptake, buffering, and detoxification to support intracellular survival while avoiding lipotoxicity. Concurrently, M. tuberculosis exports complex lipids that shape local immune responses and those in bystander cells. This minireview synthesizes recent advances in understanding the dynamic, bidirectional lipid interactions that define tuberculosis pathogenesis.
