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A mammalian nervous-system-specific plasma membrane proteasome complex that modulates neuronal function.

ABSTRACT: In the nervous system, rapidly occurring processes such as neuronal transmission and calcium signaling are affected by short-term inhibition of proteasome function. It is unclear how proteasomes are able to acutely regulate such processes, as this action is inconsistent with their canonical role in proteostasis. Here we describe a mammalian nervous-system-specific membrane proteasome complex that directly and rapidly modulates neuronal function by degrading intracellular proteins into extracellular peptides that can stimulate neuronal signaling. This proteasome complex is closely associated with neuronal plasma membranes, exposed to the extracellular space, and catalytically active. Selective inhibition of the membrane proteasome complex by a cell-impermeable proteasome inhibitor blocked the production of extracellular peptides and attenuated neuronal-activity-induced calcium signaling. Moreover, we observed that membrane-proteasome-derived peptides were sufficient to induce neuronal calcium signaling. Our discoveries challenge the prevailing notion that proteasomes function primarily to maintain proteostasis, and highlight a form of neuronal communication that takes place through a membrane proteasome complex.

SUBMITTER: Ramachandran KV

PROVIDER: S-EPMC5383508 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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A mammalian nervous-system-specific plasma membrane proteasome complex that modulates neuronal function.

Ramachandran Kapil V KV Margolis Seth S SS

Nature structural & molecular biology 20170313 4

In the nervous system, rapidly occurring processes such as neuronal transmission and calcium signaling are affected by short-term inhibition of proteasome function. It is unclear how proteasomes are able to acutely regulate such processes, as this action is inconsistent with their canonical role in proteostasis. Here we describe a mammalian nervous-system-specific membrane proteasome complex that directly and rapidly modulates neuronal function by degrading intracellular proteins into extracellu ...[more]

PMID: 28287632

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Project description:The novel neuroproteasome is localized to the neuronal plasma membrane to degrade intracellular proteins into peptides that are released to the extracellular space. Selective inhibition of this neuronal membrane proteasome (NMP) complex ceased the release of peptides and rapidly attenuated neuronal transmission. Based on these findings, we hypothesize that these neuron-specific peptides mediate a novel form of communication through unique peptide-receptor interactions to promote intracellular signaling cascades relevant to neuronal development and function. Our work indicates that NMP peptides can rapidly induce N-methyl-D-aspartate receptor (NMDAR)-dependent calcium influx from dendrites to the soma, leading to rapid and sustained phosphorylation of the well-defined activity-dependent transcription factor cAMP response element-binding protein (CREB). We also determined that the gene expression program drastically changes upon NMP peptide treatment of neurons with an increase in expression of immediate early genes (e.g., Fos, Npas4, Egr4) known to have critical neuroregulatory roles. These data support our current thinking that NMP peptides are endogenous and selective activators of synaptic NMDA receptors and are critical for promoting activity-dependent gene expression. This pathway is orthogonal to the classic neurotransmitters previously described to activate NMDARs and points to NMP and its resulting peptides as key contributors to the development and function of the nervous system. However, the unique peptide sequences leading to neuronal activation are still poorly understood. Here, we show that the NMP peptides have tremendous sequence diversity through an unbiased peptidomic approach, and the current ongoing effort is to identify unique active peptide sequences with distinct receptor specificity. Elucidating the mechanism of the NMP and its active peptide products is crucial to understanding the role of this novel signaling process in the nervous system.

Project description:Genome sequence comparisons have highlighted many novel gene families that are conserved across animal phyla but whose biological function is unknown. Here, we functionally characterize a member of one such family, the macoilins. Macoilins are characterized by several highly conserved predicted transmembrane domains towards the N-terminus and by coiled-coil regions C-terminally. They are found throughout Eumetazoa but not in other organisms. Mutants for the single Caenorhabditis elegans macoilin, maco-1, exhibit a constellation of behavioral phenotypes, including defects in aggregation, O? responses, and swimming. MACO-1 protein is expressed broadly and specifically in the nervous system and localizes to the rough endoplasmic reticulum; it is excluded from dendrites and axons. Apart from subtle synapse defects, nervous system development appears wild-type in maco-1 mutants. However, maco-1 animals are resistant to the cholinesterase inhibitor aldicarb and sensitive to levamisole, suggesting pre-synaptic defects. Using in vivo imaging, we show that macoilin is required to evoke Ca²(+) transients, at least in some neurons: in maco-1 mutants the O?-sensing neuron PQR is unable to generate a Ca²(+) response to a rise in O?. By genetically disrupting neurotransmission, we show that pre-synaptic input is not necessary for PQR to respond to O?, indicating that the response is mediated by cell-intrinsic sensory transduction and amplification. Disrupting the sodium leak channels NCA-1/NCA-2, or the N-,P/Q,R-type voltage-gated Ca²(+) channels, also fails to disrupt Ca²(+) responses in the PQR cell body to O? stimuli. By contrast, mutations in egl-19, which encodes the only Caenorhabditis elegans L-type voltage-gated Ca²(+) channel ?1 subunit, recapitulate the Ca²(+) response defect we see in maco-1 mutants, although we do not see defects in localization of EGL-19. Together, our data suggest that macoilin acts in the ER to regulate assembly or traffic of ion channels or ion channel regulators.

Dataset Information

A mammalian nervous-system-specific plasma membrane proteasome complex that modulates neuronal function.

Publications

A mammalian nervous-system-specific plasma membrane proteasome complex that modulates neuronal function.

Similar Datasets

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