NRA-2, a Nicalin Homolog, Regulates Neuronal Death by Controlling Surface Localization of Toxic Caenorhabditis elegans DEG/ENaC Channels

Kamat, Shaunak; Yeola, Shrutika; Zhang, Wenying; Bianchi, Laura; Driscoll, Monica

doi:10.1074/jbc.m113.533695

Cited by 12 publications

(12 citation statements)

References 44 publications

(31 reference statements)

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“…Our single molecule analysis (above) showed that MEC-4 can form homotrimers on its own or 4:4:10 heterotrimers when coexpressed with MEC-10. In vivo, MEC-10::GFP was previously shown to be predominantly localized in the TRN cell body and to have diffuse expression in the neurite (20,26). We confirmed this (Fig.…”

Section: Mec-6 Does Not Tightly Associate With the Mec-4/mec-10 Channelsupporting

confidence: 79%

Subunit composition of a DEG/ENaC mechanosensory channel of Caenorhabditis elegans

Chen

Bharill

Isacoff

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Caenorhabditis elegans senses gentle touch in the six touch receptor neurons (TRNs) using a mechanotransduction complex that contains the pore-forming degenerin/epithelial sodium channel (DEG/ENaC) proteins MEC-4 and MEC-10. Past work has suggested these proteins interact with the paraoxonase-like MEC-6 and the cholesterol-binding stomatin-like MEC-2 proteins. Using single molecule optical imaging in Xenopus oocytes, we found that MEC-4 forms homotrimers and MEC-4 and MEC-10 form 4:4:10 heterotrimers. MEC-6 and MEC-2 do not associate tightly with these trimers and do not influence trimer stoichiometry, indicating that they are not part of the core channel transduction complex. Consistent with the in vitro data, MEC-10, but not MEC-6, formed puncta in TRN neurites that colocalize with MEC-4 when MEC-4 is overexpressed in the TRNs. mechanosensory channels | DEG/ENaC proteins | channel stoichiometry

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Section: Mec-6 Does Not Tightly Associate With the Mec-4/mec-10 Channelsupporting

confidence: 79%

Subunit composition of a DEG/ENaC mechanosensory channel of Caenorhabditis elegans

Chen

Bharill

Isacoff

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…CCDC47, Nicalin, TMEM147 and NOMO are abundant ER-localized proteins, conserved across eukaryotes, widely expressed in human tissues, and associated with several human diseases ( Itzhak et al, 2016 ; Burdon et al, 2011 ; Sharma et al, 2012 ; Xin et al, 2010 ; Caglayan et al, 2013 ; Alanay et al, 2014 ; Li et al, 2019 ; Reuter et al, 2017 ; Morimoto et al, 2018 ). Although their functions remain obscure, CCDC47 has been linked to various membrane-associated processes ( Morimoto et al, 2018 ; Zhang et al, 2007 ; Konno et al, 2012 ; Thapa et al, 2018 ; Yamamoto et al, 2014 ), and the Nicalin-TMEM147-NOMO complex has been proposed to regulate subunit assembly and localization of several cell surface receptors and ion channels ( Almedom et al, 2009 ; Gottschalk et al, 2005 ; Kamat et al, 2014 ; Rosemond et al, 2011 ). More recently, all four genes were identified in a genome-wide screen for factors that impair surface expression of a mutant TRP channel ( Talbot et al, 2019 ).…”

Section: Resultsmentioning

confidence: 99%

“…At the cellular level, disrupting TMCO1, CCDC47, Nicalin, TMEM147 or NOMO leads to reduced fitness ( Wang et al, 2015 ). Cells lacking CCDC47 show attenuated ERAD ( Yamamoto et al, 2014 ) and impaired Ca 2+ signaling ( Zhang et al, 2007 ; Konno et al, 2012 ), while the Nicalin-TMEM147-NOMO complex is linked to Nodal signaling ( Haffner et al, 2004 ) and altered localization and subunit composition of some multi-pass membrane proteins ( Almedom et al, 2009 ; Kamat et al, 2014 ; Rosemond et al, 2011 ). Cells lacking TMCO1 show defects in Ca 2+ handling, which has led to the proposal that TMCO1 functions as a Ca 2+ -channel ( Wang et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

An ER translocon for multi-pass membrane protein biogenesis

McGilvray

Anghel

Sundaram

et al. 2020

eLife

101

136

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Membrane proteins with multiple transmembrane domains play critical roles in cell physiology, but little is known about the machinery coordinating their biogenesis at the endoplasmic reticulum. Here we describe a ~360 kDa ribosome-associated complex comprising the core Sec61 channel and five accessory factors: TMCO1, CCDC47 and the Nicalin-TMEM147-NOMO complex. Cryo-electron microscopy reveals a large assembly at the ribosome exit tunnel organized around a central membrane cavity. Similar to protein-conducting channels that facilitate movement of transmembrane segments, cytosolic and luminal funnels in TMCO1 and TMEM147, respectively, suggest routes into the central membrane cavity. High-throughput mRNA sequencing shows selective translocon engagement with hundreds of different multi-pass membrane proteins. Consistent with a role in multi-pass membrane protein biogenesis, cells lacking different accessory components show reduced levels of one such client, the glutamate transporter EAAT1. These results identify a new human translocon and provide a molecular framework for understanding its role in multi-pass membrane protein biogenesis.

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“…The ability of misfolded proteins to be eliminated from the ER is an essential function in adaptation to ER stress. NRA-2 has been characterized as an ER protein that regulates neuronal death ( Kamat et al 2014 ); to date, no function in the germ line has been characterized. It will be interesting to determine if and how the ER is affected in arrested oocytes after knockdown of each of these four genes.…”

Section: Resultsmentioning

confidence: 99%

RNAi Screen Identifies Novel Regulators of RNP Granules in theCaenorhabditis elegansGerm Line

Wood

Hollis

Severance

et al. 2016

G3 Genes|Genomes|Genetics

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Complexes of RNA and RNA binding proteins form large-scale supramolecular structures under many cellular contexts. In Caenorhabditis elegans, small germ granules are present in the germ line that share characteristics with liquid droplets that undergo phase transitions. In meiotically-arrested oocytes of middle-aged hermaphrodites, the germ granules appear to aggregate or condense into large assemblies of RNA-binding proteins and maternal mRNAs. Prior characterization of the assembly of large-scale RNP structures via candidate approaches has identified a small number of regulators of phase transitions in the C. elegans germ line; however, the assembly, function, and regulation of these large RNP assemblies remain incompletely understood. To identify genes that promote remodeling and assembly of large RNP granules in meiotically-arrested oocytes, we performed a targeted, functional RNAi screen and identified over 300 genes that regulate the assembly of the RNA-binding protein MEX-3 into large granules. Among the most common GO classes are several categories related to RNA biology, as well as novel categories such as cell cortex, ER, and chromosome segregation. We found that arrested oocytes that fail to localize MEX-3 into cortical granules display reduced oocyte quality, consistent with the idea that the larger RNP assemblies promote oocyte quality when fertilization is delayed. Interestingly, a relatively small number of genes overlap with the regulators of germ granule assembly during normal development, or with the regulators of solid RNP granules in cgh-1 oocytes, suggesting fundamental differences in the regulation of RNP granule phase transitions during meiotic arrest.

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NRA-2, a Nicalin Homolog, Regulates Neuronal Death by Controlling Surface Localization of Toxic Caenorhabditis elegans DEG/ENaC Channels

Cited by 12 publications

References 44 publications

Subunit composition of a DEG/ENaC mechanosensory channel of Caenorhabditis elegans

Subunit composition of a DEG/ENaC mechanosensory channel of Caenorhabditis elegans

An ER translocon for multi-pass membrane protein biogenesis

RNAi Screen Identifies Novel Regulators of RNP Granules in theCaenorhabditis elegansGerm Line

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