The nociceptive activity of peripheral sensory neurons is modulated by the neuronal membrane proteasome

Proteasomes are critical for peripheral nervous system (PNS) function. Here, we investigate mammalian PNS proteasomes and reveal the presence of the neuronal membrane proteasome (NMP). We show that specific inhibition of the NMP on distal nerve fibers innervating the mouse hind paw leads to reduction in mechanical and pain sensitivity. Through investigating PNS NMPs, we demonstrate their presence on the somata and proximal and distal axons of a subset of dorsal root ganglion (DRG) neurons. Single-cell RNA sequencing experiments reveal that the NMP-expressing DRGs are primarily MrgprA3+ and Cysltr2+. NMP inhibition in DRG cultures leads to cell-autonomous and non-cell-autonomous changes in Ca2+ signaling induced by KCl depolarization, αβ-meATP, or the pruritogen histamine. Taken together, these data support a model whereby NMPs are expressed on a subset of somatosensory DRGs to modulate signaling between neurons of distinct sensory modalities and indicate the NMP as a potential target for controlling pain. [Display omitted] •The neuronal membrane proteasome (NMP) is found in peripheral somatosensory neurons•The NMP selectively localizes to specific types of somatosensory neurons•The NMP mediates crosstalk between sensory neurons to modulate sensitivity to stimulation•Inhibition of the NMP reduces sensitivity to mechanical and painful stimuli Proteasomes are critical for sensory neuron function. Villalón Landeros et al. uncover a specialized proteasome in somatosensory neurons called the neuronal membrane proteasome (NMP). The NMP mediates crosstalk between somatosensory neurons to modulate sensitivity to stimulation. Inhibition of the NMP reduces sensitivity to mechanical and painful stimuli in vivo.