Protein & Cell最新文献

Neurons face a fundamental proteostasis challenge: synapses and axons located far from the soma must rapidly remodel their proteome during activity, stress, and development. While local protein synthesis has long been recognized as essential for meeting these demands, classical models largely focused on ribonucleoprotein (RNP) granules as autonomous carriers of translationally silent mRNAs, treating membranous organelles as parallel logistics or metabolic systems. Recent work overturns this view, revealing that endosomes, lysosomes, axonal endoplasmic reticulum, mitochondria, and their contact sites actively function as mobile translation platforms. In this review, we propose an RBP-centered framework in which phase-separated condensates physically tether specific mRNA cohorts to organelle surfaces, coupling mRNA transport, translational control, and organelle dynamics into a unified network. By organizing recent discoveries into functional modules-long-range transport, localized translation, and stress buffering-this neuron-focused framework identifies organelle-anchored translation factories as a unifying principle of synaptic proteostasis and a broadly applicable design paradigm for highly polarized cells.

The innate immune sensor AIM2 detects cytosolic DNA and initiates inflammatory responses, yet its activation mechanism remains incompletely understood. Here, we show that AIM2 undergoes liquid-liquid phase separation upon DNA binding, forming dynamic condensates both in vitro and in cells. These condensates serve as platforms for inflammasome and PANoptosome assembly, promoting immune activation across multiple pathways. Direct structural determination from condensates reveals the assembly of active-form ASC filaments. Mechanistically, liquid-phase condensation is governed by multivalent interactions involving different AIM2 domains, including previously uncharacterized regions and species-specific elements. In vitro and in vivo assays show that mutants specifically disrupting condensation impair immune complex assembly, cell death initiation, antimicrobial defense, and intestinal homeostasis. Moreover, AIM2-DNA condensates function as regulatory hubs targeted by host- and pathogen-derived factors to balance immune homeostasis or facilitate immune evasion. These findings establish liquid-phase condensation as a fundamental mechanism of AIM2 activation and a potential therapeutic target.

A portable, universal, easy-to-preserve alternative of human red blood cells (RBC) has been pursued for decades in order to expand the limited blood supply, with Hemoglobin-Based Oxygen Carrier (HBOC) being one of the most promising techniques. Through two generations of development, various HBOC products were designed to emulate the natural RBCs with better biochemical and physical properties, but their over-ambitious product positioning and irrational clinical designs impeded their final approval. Now in its third generation, HBOC is finally poised for its commercialization with clearer views on a proper indication for use. Here, we review the development of HBOC, update the current pipeline and outline key lessons we have learned through past failures. We also specify its use scenario and propose future development to provide a more complete picture of the past, present and future of HBOC.

Aging of the male reproductive system is characterized by declining fertility, with epididymal dysfunction being a critical yet poorly understood contributor. Through a multimodal analysis in non-human primates that integrated histology and transcriptomics, we delineated a coherent epididymal aging phenotype encompassing epithelial senescence, chronic inflammation, fibrosis, and functional decline. Single-nucleus transcriptomics revealed principal cells (PCs) as the predominant and most transcriptionally perturbed epithelial cell type. Within PCs, the longevity-associated transcription factor FOXO1 was markedly downregulated with age. Functional studies in human epididymal epithelial cells demonstrated that FOXO1 deficiency drives cellular senescence. Mechanistically, FOXO1 transcriptionally activates LHX1, and this axis is essential for counteracting senescence. Furthermore, intervention with senescence-resistant mesenchymal progenitor cells or their exosomes mitigated epididymal aging phenotypes and restored FOXO1 expression in vivo and in vitro. Our study establishes the FOXO1-LHX1 axis as a key protective pathway against primate epididymal aging, providing mechanistic insights and potential therapeutic targets for preserving male reproductive health.

The bacterial flagellar motor is a protein nanomachine that rotates the flagellum to facilitate bacterial motility. These motors exhibit structural diversity among species, enabling the transmission of varying torques to flagellar filaments to grant bacteria diverse swimming capabilities. Compared to peritrichous flagellar motors, polar flagellar motors are faster machines that transmit higher torque to drive high-speed motility in liquids and empower swimming in viscous environments. However, structural basis of high-torque transmission of the polar flagellar motors is still unclear. Here we present a cryo-electron microscopy structure of the polar flagellar motor in complex with the hook from Vibrio alginolyticus, comprising 295 subunits from 18 proteins. Compared to the peritrichous flagellar rod, this structure reveals an increased number of inter-subunit interactions in the rod of the polar flagellar motor. Nine phospholipid molecules insert into the interface between the export apparatus and the proximal rod. The LP ring contains more electrostatic charges on the inner surface and has fewer physical contacts with the rod, while the HT ring tightly binds to the outer surface of the LP ring. FlrP, a protein of previously unknown function, is identified as a new component of the polar flagellar motor, and extensively participates in the interactions of 15 FliF peptides of the MS ring with the rod. In contrast to that in the peritrichous flagellum, the hook in the polar flagellum has two different conformational states, L- and R-types. These findings provide unprecedented insights into structural adaptations of the bacterial polar flagellar motors for high-torque transmission.