Actin-Independent Behavior and Membrane Deformation Exhibited by the Four-Transmembrane Protein M6a

Sato, Yasufumi; Watanabe, Naoki; Fukushima, Nanae; Mita, Sakura; Hirata, Tatsumi

doi:10.1371/journal.pone.0026702

Cited by 17 publications

(14 citation statements)

References 63 publications

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“…We postulate that the GPM6 glycoproteins may form a protein pore, perhaps through oligomeric interactions, which have been proposed previously 35,44 . In the right conformation, proteasomes binding to pore-containing membrane proteins could give proteasomes a hydrophilic binding surface to the hydrophobic plasma membrane, allowing the proteasome to gain access to the extracellular space.…”

Section: Discussionsupporting

confidence: 55%

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

Ramachandran

Margolis

2017

Nat Struct Mol Biol

117

133

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In the nervous system, rapidly occurring processes such as neuronal transmission and calcium signaling are affected by short-term inhibition of proteasome function. It remains unclear how proteasomes can acutely regulate such processes, as this is inconsistent with their canonical role in proteostasis. Here, we made the discovery of 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 tightly associated with neuronal plasma membranes, exposed to the extracellular space, and catalytically active. Selective inhibition of this membrane proteasome complex by a cell-impermeable proteasome inhibitor blocked extracellular peptide production and attenuated neuronal activity-induced calcium signaling. Moreover, membrane proteasome-derived peptides are sufficient to induce neuronal calcium signaling. Our discoveries challenge the prevailing notion that proteasomes primarily function to maintain proteostasis, and highlight a form of neuronal communication through a membrane proteasome complex.

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Section: Discussionsupporting

confidence: 55%

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

Ramachandran

Margolis

2017

Nat Struct Mol Biol

117

133

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“…In conclusion, in the last 10 years, various cellular, anatomical, and pathological alterations have been associated with neuronal glycoprotein M6a, whose mechanism of action is still unknown. Sato et al described the critical role of the TMD1 of M6a in inducing tubular processes in COS-7 cells (Sato et al 2011b). This work provides the first evidence of the critical role of certain residues located on TMD2 and TMD4 of M6a in the mechanism of action and the potential risk of the SNPs reported here, particularly SNP3.…”

Section: ###supporting

confidence: 65%

Filopodia formation driven by membrane glycoprotein M6a depends on the interaction of its transmembrane domains

Formoso

Garcia

Frasch

et al. 2015

Journal of Neurochemistry

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Membrane glycoprotein M6a, which belongs to the tetraspan proteolipid protein family, promotes structural plasticity in neurons and cell lines by unknown mechanisms. This glycoprotein is encoded by Gpm6a, a stress-regulated gene. The hippocampus of animals chronically stressed by either psychosocial or physical stressors shows decreased M6a expression. Stressed Gpm6a-null mice develop a claustrophobia-like phenotype. In humans, de novo duplication of GPM6A results in learning/behavioral abnormalities, and two single-nucleotide polymorphisms (SNPs) in the non-coding region are linked to mood disorders. Here, we studied M6a dimerization in neuronal membranes and its functional relevance. We showed that the self-interaction of M6a transmembrane domains (TMDs) might be driving M6a dimerization, which is required to induce filopodia formation. Glycine mutants located in TMD2 and TMD4 of M6a affected its dimerization, thus preventing M6a-induced filopodia formation in neurons. In silico analysis of three non-synonymous SNPs located in the coding region of TMDs suggested that these mutations induce protein instability. Indeed, these SNPs prevented M6a from being functional in neurons, owing to decreased stability, dimerization or improper folding. Interestingly, SNP3 (W141R), which caused endoplasmic reticulum retention, is equivalent to that mutated in PLP1, W161L, which causes demyelinating Pelizaeus-Merzbacher disease.

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“…Previous study showed that the over-expression of M6a enhanced the formation of membrane protrusions (Sato et al, 2011b) and filopodia/spine (Alfonso et al, 2005;Brocco et al, 2010).…”

Section: Functional Domains Of M6a For the Axonal Growthmentioning

confidence: 92%

“…For the formation of membrane protrusions, the N-terminus domain (amino acid 1-62) of M6a is required (Sato et al, 2011b). For the formation of filopodia/spine, the second extracellular domain (C174 and C192) is essential (Fuchsova et al, 2009).…”

Section: Functional Domains Of M6a For the Axonal Growthmentioning

confidence: 99%

M6 proteins regulate axon outgrowth in mouse callosal neurons

Mita

Saga

Werner³

et al. 2010

Neuroscience Research

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Corpus callosum (CC) is the largest fiber tract in the human brain that connects the left and right cerebral hemispheres. The absence of the CC results in impairment of higher-order cognitive functions because interhemispheric transfer of information is disrupted. The formation of the CC is intricately regulated by a large number of molecules, which have not been fully characterized, while actively searched. In this study, I showed that additional molecules, M6 proteins, are also involved in the CC development.M6 proteins consist of M6a and M6b, highly homologous four-transmembrane proteins. M6a was originally found by the antibody screening for candidate molecules that are involved in guidance of axons. Previously, we found that when anti-M6a antibody binds to M6a protein in cultured neurons, the axons stall the elongation. Therefore, it seemed that M6a is involved in axon elongation of developing neurons. However, no study has so far examined the function of M6 proteins in vivo. To address this issue, I analyzed brain morphology and axonal projections in knockout mice for the M6a and M6b genes.First, to assess whether the two M6 proteins have redundant functions, I investigated expression patterns of M6a and M6b proteins in the wildtype mouse brains during developmental stages, using a newly prepared anti-M6b specific antibody. M6a was expressed mainly in growing axons as previously reported. The new anti-M6b antibody revealed that M6b was well co-localized with M6a in these axons. The expression level of M6b on the axons appeared lower at E14.5 compared with M6a, and subsequently intensified at E16.5 and P0, displaying comparable overlapping patterns with M6a. I also examined the subcellular distribution of M6 proteins in neurons in dissociated culture. As described previously, M6a protein was enriched in the edge of growth cones and the shaft filopodia of axons in cultured neurons. M6b protein was also expressed in the growth cones and the shaft filopodia, and co- However, the size of the CC bundle was abnormally small in the M6a-/-M6b-/-knockout mice.This hypoplasia in the CC was not clear at early developmental stages (E14.5, E16.5 and P0), but became obvious by P7 and throughout life. I quantified the size of the CC in wild-type, single and double mutant mice at P7, and found that the defect was most pronounced in the double knockout mice, indicating the redundant function of the two M6 proteins.I considered the following three possibilities to explain the smaller CC bundles in the double knockout mice. 1) the number of the callosal neurons is reduced.2) The axons of the callosal neurons are misdirected from callosal pathway.3) The axon outgrowth is impaired in the callosal neurons.First, to evaluate the possibility 1), I measured the density of cortical neurons in the mutant cortex in the motor, somatosensory, and visual areas. The neural density of the double mutant cortex was comparable to that of the wild-type. This result suggests that the number of callosal neurons was not reduced in the M6a...

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Actin-Independent Behavior and Membrane Deformation Exhibited by the Four-Transmembrane Protein M6a

Cited by 17 publications

References 63 publications

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

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

Filopodia formation driven by membrane glycoprotein M6a depends on the interaction of its transmembrane domains

M6 proteins regulate axon outgrowth in mouse callosal neurons

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