Eukaryotic cells have evolved highly orchestrated protein catabolic machineries responsible for the timely and selective disposal of proteins and organelles, thereby ensuring amino acid recycling. However, how protein degradation is coordinated with amino acid supply and protein synthesis has remained largely elusive. Here we show that the mammalian proteasome undergoes liquid-liquid phase separation in the nucleus upon amino acid deprivation. We termed these proteasome condensates SIPAN (Starvation-Induced Proteasome Assemblies in the Nucleus) and show that these are a common response of mammalian cells to amino acid deprivation. SIPAN undergo fusion events, rapidly exchange proteasome particles with the surrounding milieu and quickly dissolve following amino acid replenishment. We further show that: (i) SIPAN contain K48-conjugated ubiquitin, (ii) proteasome inhibition accelerates SIPAN formation, (iii) deubiquitinase inhibition prevents SIPAN resolution and (iv) RAD23B proteasome shuttling factor is required for SIPAN formation. Finally, SIPAN formation is associated with decreased cell survival and p53-mediated apoptosis, which might contribute to tissue fitness in diverse pathophysiological conditions.

transducers. For example, transient receptor potential vanilloid type 1 (TRPV1) is an ion channel receptor specialized in noxious heat sensing (≈42-45 °C) and expressed by ≈40% of nociceptors. Once activated, it triggers the uptake of sodium and calcium through its ionic pore, leading to neuron depolarization and to neuropeptides release. [3] The immune and sensory nervous systems work in concert to promote host defense and homeostasis. [4] They share metabolic pathways [5] and interact through a common language of receptors, cytokines, and neuropeptides. While this bidirectional communication is often adaptive, helping to protect from danger, in other settings, it drives chronic inflammatory pathologies. [2] Thus, the somatosensory nervous system is anatomically positioned in primary and secondary lymphoid tissues, and mucosa to modulate immunity. As such, nociceptors were found to detect immunocytesreleased interleukin (IL), such as IL-23 produced during psoriasis, IL-4 released in the context of atopic dermatitis as well as IL-5 and immunoglobulin E (IgE) released during allergic asthma. [1] Such interaction results in pain hypersensitivity, but also lowers the nociceptor firing threshold and leads to neuropeptide release. [4] These findings strongly suggest that nociceptor neurons are critical drivers of allergy and inflammation in a variety of diseases by responding to immunocytes produced cues. Theselective silencing of nociceptors' response to such cytokines can transform established therapeutic approaches.The sensory nervous and immune systems work in concert to preserve homeostasis. While this endogenous interplay protects from danger, it may drive chronic pathologies. Currently, genetic engineering of neurons remains the primary approach to interfere selectively with this potentially deleterious interplay. However, such manipulations are not feasible in a clinical setting. Here, this work reports a nanotechnology-enabled concept to silence subsets of unmodified nociceptor neurons that exploits their ability to respond to heat via the transient receptor potential vanilloid type 1 (TRPV1) channel. This strategy uses laser stimulation of antibody-coated gold nanoparticles to heat-activate TRPV1, turning this channel into a cell-specific drug-entry port. This delivery method allows transport of a charged cationic derivative of an N-type calcium channel blocker (CNCB-2) into targeted sensory fibers. CNCB-2 delivery blocks neuronal calcium currents and neuropeptides release, resulting in targeted silencing of nociceptors. Finally, this work demonstrates the ability of the approach to probe neuro-immune crosstalk by targeting cytokine-responsive nociceptors and by successfully preventing nociceptorinduced CD8 + T-cells polarization. Overall, this work constitutes the first demonstration of targeted silencing of nociceptor neuron subsets without requiring genetic modification, establishing a strategy for interfering with deleterious neuro-immune interplays.

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The genetic alterations contributing to migration proficiency, a phenotypic hallmark of metastatic cells required for colonizing distant organs, remain poorly defined. Here, we used single-cell magneto-optical capture (scMOCa) to isolate fast cells from heterogeneous breast cancer cell populations, based on their migratory ability alone. We show that captured fast cell subpopulations retain higher migration speed and focal adhesion dynamics over many generations due to a motility-related transcriptomic profile. Upregulated genes in fast selected cells encoded integrin subunits, proto-cadherins and numerous other genes associated with cell migration. Dysregulation of several of these genes correlated with poor survival outcomes in patients, while primary tumors established from fast cells generated a higher number of circulating tumor cells and soft tissue metastases in vivo. Subpopulations of cells selected for a highly migratory phenotype demonstrated an increased fitness for metastasis.

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