RNF-121 Is an Endoplasmic Reticulum-Membrane E3 Ubiquitin Ligase Involved in the Regulation of β-Integrin

Darom, Amir; Bening-Abu-Shach, Ulrike; Broday, Limor

doi:10.1091/mbc.e09-09-0774

Cited by 39 publications

(41 citation statements)

References 63 publications

(85 reference statements)

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“…The mutant locus was meiotically mapped onto chromosome 21 near rnf121 (Fig. S2A), a 331-aa ER-associated E3-ubiquitin ligase (18). RNF121 is a six-transmembrane domain protein whose amino and carboxyl termini are located within the ER (19).…”

Section: Resultsmentioning

confidence: 99%

RING finger protein 121 facilitates the degradation and membrane localization of voltage-gated sodium channels

Ogino

Low

Yamada

et al. 2015

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

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Following their synthesis in the endoplasmic reticulum (ER), voltagegated sodium channels (Na V ) are transported to the membranes of excitable cells, where they often cluster, such as at the axon initial segment of neurons. Although the mechanisms by which Na V channels form and maintain clusters have been extensively examined, the processes that govern their transport and degradation have received less attention. Our entry into the study of these processes began with the isolation of a new allele of the zebrafish mutant alligator, which we found to be caused by mutations in the gene encoding really interesting new gene (RING) finger protein 121 (RNF121), an E3-ubiquitin ligase present in the ER and cis-Golgi compartments. Here we demonstrate that RNF121 facilitates two opposing fates of Na V channels: (i) ubiquitin-mediated proteasome degradation and (ii) membrane localization when coexpressed with auxiliary Na V β subunits. Collectively, these results indicate that RNF121 participates in the quality control of Na V channels during their synthesis and subsequent transport to the membrane.oltage-gated sodium channels (Na V ) are large (∼230 kDa) multipass transmembrane proteins (1). The Na V channel family is comprised of nine members (Na V 1.1-Na V 1.9), whose activity typically underlies the rising phase of action potentials in excitable cells. In excitable cells, Na V channels form complexes with auxiliary β subunits (Na V β 1-4 ) in the Golgi apparatus (2), a process that enhances the kinetics and membrane localization of Na V channels (3, 4). In addition to these roles, several Na V β subunits also function as cell adhesion molecules independent of Na V channels (5). At the axon initial segment (AIS) and nodes of Ranvier of neurons, Na V channels form clusters that facilitate the generation and propagation of action potentials. Although the molecular basis of Na V clustering at these sites has been extensively studied (6), the transport of Na V channels to these sites has been less explored. For instance, to date, only the annexin II light chain (p11) has been shown to associate with and facilitate the transport of Na V 1.8 to the plasma membrane (7). Furthermore, subsequent efforts revealed that p11 acts only on Na V 1.8 (8). Thus, the transport of other Na V channels remains unclear.In zebrafish, several studies have explored the contribution of Na V channels and their auxiliary Na V β subunits through the use of forward and reverse genetics. In brief, impairments in Na V 1.1, Na V 1.6a, and Na V β 1b have been shown to diminish touch-evoked escape responses and Na V channel activity in Rohon-Beard (RB) sensory neurons (9-11). In addition, two other mutants identified in forward genetic screens have been shown to affect Na V channel activity indirectly. The first, pigu, arises from a mutation in a GPItransamidase necessary for the proper localization of Na V channels (12). Although the genetic locus of the second mutation, macho (13,14), has yet to be identified, rough mapping indicates that it lies with...

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Section: Resultsmentioning

confidence: 99%

RING finger protein 121 facilitates the degradation and membrane localization of voltage-gated sodium channels

Ogino

Low

Yamada

et al. 2015

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

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“…One upregulated gene (GS_19094) was associated with RNA processing (“RNA-binding protein 5/10”, K13094, related to intron splicing), and the seven other genes have a variety of functions with no obvious theme, including a dopamine receptor (GS_19561), a sulfate permease (GS_00322), and an aconitate hydratase (GS_09209), while the most significantly upregulated gene in the set (GS_11054) has no functional annotation assigned. The four genes downregulated by hsiRNA treatments in both the anterior and posterior intestine included: (i) GS_04133, which has no functional annotation, but was previously predicted to be a target for endogenous miRNA silencing in the A. suum intestine (Gao et al, 2016); (ii) GS_13545, an RNA polymerase II for which the C. elegans ortholog ( rpb-12 ) was used as a non-variable control gene in other studies (Ventura et al, 2009; Darom et al, 2010); (iii) GS_21168, a C-type lectin, and (iv) GS_05428, which has no informative functional information.…”

Section: Resultsmentioning

confidence: 99%

Direct experimental manipulation of intestinal cells in Ascaris suum , with minor influences on the global transcriptome

Rosa

McNulty

Mitreva

et al. 2017

International Journal for Parasitology

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Ascaris suum provides a powerful model for studying parasitic nematodes, including individual tissues such as the intestine, an established target for anthelmintic treatments. Here, we add a valuable experimental component to our existing functional, proteomic, transcriptomic and phylogenomic studies of the Ascaris suum intestine, by developing a method to manipulate intestinal cell functions via direct delivery of experimental treatments (in this case, double-stranded (ds)RNA) to the apical intestinal membrane. We developed an intestinal perfusion method for direct, controlled delivery of dsRNA/heterogeneous small interfering (hsi) RNA into the intestinal lumen for experimentation. RNA-Seq (22 samples) was used to assess influences of the method on global intestinal gene expression. Successful mRNA-specific knockdown in intestinal cells of adult A. suum was accomplished with this new experimental method. Global transcriptional profiling confirmed that targeted transcripts were knocked down more significantly than any others, with only 12 (0.07% of all genes) or 238 (1.3%) off-target gene transcripts consistently differentially regulated by dsRNA treatment or the perfusion experimental design, respectively (after 24 h). The system supports controlled, effective delivery of treatments (dsRNA/hsiRNA) to the apical intestinal membrane with relatively minor off-target effects, and builds on our experimental model to dissect A. suum intestinal cell functions with broad relevance to parasitic nematodes.

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“…Subsequently, partial degrading costameric connections result in the reduced linkage of intermediate filament proteins in the muscle cell (Riley et al, 1988;Hilenski et al, 1992;Sekikawa et al, 2000Sekikawa et al, , 2001. Moreover, integrins that link the cytoskeleton to the extracellular matrix, are also a target of the ubiquitinproteasome system (Darom et al, 2010;Lobert and Stenmark, 2010). The degradation of integrins forms cracks between cell membrane that were termed drip channels.…”

Section: Discussionmentioning

confidence: 99%

Novel SNPs of the porcine TRIP12 are associated with water holding capacity of meat

Loan¹,

Muráni²,

Maak³

et al. 2013

CZECH J ANIM SCI

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Degradation of proteins during maturation of meat, mediated by the calpain/calpastatin system and the ubiquitination system, largely affects the tenderness and the water holding capacity (WHC) of meat. The thyroid hormone receptor interacting protein 12 (TRIP12) is known as a HECT domain-containing E3 ubiquitin-protein ligase that recognizes protein substrates for ubiquitination. This study aims to identify polymorphisms of the TRIP12 gene and to evaluate the relationship between genotype, transcript abundance, and meat quality traits in pigs. Two synonymous SNPs (XM_003484315.1:c.2211T>C, c.4957A>C) were identified that segregated among animals of herds of the breed German Landrace (DL, n = 269) and the commercial crossbreed of Pietrain × (German Large White × German Landrace) (PiF1, n = 300). Statistical analysis revealed associations between TRIP12 polymorphisms and the organismal traits related to water holding capacity, i.e. conductivity 45 min postmortem (CON 1 , P < 0.1) and pH 24 h postmortem (pH 24 , P < 0.1). Haplotype analysis revealed consistent effects on muscle CON 1 in the two populations (P < 0.1). Carriers of the minor alleles C at the two polymorphic sites tended to have higher transcript abundance as well as higher water holding capacity. The integrated analysis of genotypic and haplotypic variation, transcript abundance, and technological parameters of WHC indicates that the XM_003484315.1:c.2211T>C and c.4957A>C of TRIP12 are in linkage disequilibrium with a causal factor located in a cis-regulatory region, which affects in the first instance gene expression and in the second traits related to water holding capacity. Our results provide statistical-genetical evidence supporting TRIP12 as a functional candidate gene for water holding capacity of porcine M. longissimus dorsi.

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RNF-121 Is an Endoplasmic Reticulum-Membrane E3 Ubiquitin Ligase Involved in the Regulation of β-Integrin

Cited by 39 publications

References 63 publications

RING finger protein 121 facilitates the degradation and membrane localization of voltage-gated sodium channels

RING finger protein 121 facilitates the degradation and membrane localization of voltage-gated sodium channels

Direct experimental manipulation of intestinal cells in Ascaris suum , with minor influences on the global transcriptome

Novel SNPs of the porcine TRIP12 are associated with water holding capacity of meat

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