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Functional characterization of two secreted SEL1L isoforms capable of exporting unassembled substrate.

ABSTRACT: SEL1L-A, a transmembrane glycoprotein residing in the endoplasmic reticulum (ER), is a component of the ER-associated degradation (ERAD) pathway. Alternative splicing generates two smaller SEL1L isoforms, -B and -C, that lack the SEL1L-A membrane-spanning region but retain some sel-1-like repeats, known to be involved in multi-protein interactions and signal transduction. In this study the functional characteristics of SEL1L-B and -C were investigated in human cell models. We show that these two isoforms are induced upon ER stress and activation of the unfolded protein response, together with SEL1L-A. Using transient transfection experiments (based on wild-type and mutant SEL1L constructs) combined with several biochemical tests we show that SEL1L-B and, more prominently, SEL1L-C are secreted glycoproteins. Although SEL1L-C is in monomeric form, SEL1L-B is engaged in intramolecular/intermolecular disulfide bonds. Both isoforms localize in secretory and degradative cellular compartments and in areas of cell-cell contact. However, whereas SEL1L-B is mainly associated with membranes, SEL1L-C shows the typical intralumenal localization of soluble proteins and is present in intercellular spaces. Furthermore, because of its peroxisomal domain, SEL1L-C localizes to peroxisomes. Both SEL1L-B and -C are involved in sorting and exporting unassembled Ig-mu(s) but do not affect two other ERAD substrates, the null Hong Kong variant of alpha(1)-antitrypsin, and mutant alpha(1)-AT Z. Overall these findings suggest that SEL1L-B and -C participate to novel molecular pathways that, in parallel with ERAD, contribute to the disposure of misfolded/unfolded or orphan proteins through degradation or secretion.

SUBMITTER: Cattaneo M

PROVIDER: S-EPMC2670146 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Functional characterization of two secreted SEL1L isoforms capable of exporting unassembled substrate.

Cattaneo Monica M Lotti Lavinia Vittoria LV Martino Simone S Cardano Marina M Orlandi Rosaria R Mariani-Costantini Renato R Biunno Ida I

The Journal of biological chemistry 20090209 17

SEL1L-A, a transmembrane glycoprotein residing in the endoplasmic reticulum (ER), is a component of the ER-associated degradation (ERAD) pathway. Alternative splicing generates two smaller SEL1L isoforms, -B and -C, that lack the SEL1L-A membrane-spanning region but retain some sel-1-like repeats, known to be involved in multi-protein interactions and signal transduction. In this study the functional characteristics of SEL1L-B and -C were investigated in human cell models. We show that these two ...[more]

PMID: 19204006

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Project description:BackgroundThe annotation of biomolecular functions is an essential step in the analysis of newly sequenced organisms. Usually, the functions are inferred from predicted genes on the genome using homology search techniques. A high quality genomic sequence is an important prerequisite which, however, is difficult to achieve for certain organisms, such as hybrids or organisms with a large genome. For functional analysis it is also possible to use a de novo transcriptome assembly but the computational requirements can be demanding. Up to now, it is unclear how much of the functional repertoire of an organism can be reliably predicted from unassembled RNA-seq short reads alone.ResultsWe have conducted a study to investigate to what degree it is possible to reconstruct the functional profile of an organism from unassembled transcriptome data. We simulated the de novo prediction of biomolecular functions for Arabidopsis thaliana using a comprehensive RNA-seq data set. We evaluated the prediction performance using several homology search methods in combination with different evidence measures. For the decision on the presence or absence of a particular function under noisy conditions we propose a statistical mixture model enabling unsupervised estimation of a detection threshold. Our results indicate that the prediction of the biomolecular functions from the KEGG database is possible with a high sensitivity up to 94 percent. In this setting, the application of the mixture model for automatic threshold calibration allowed the reduction of the falsely predicted functions down to 4 percent. Furthermore, we found that our statistical approach even outperforms the prediction from a de novo transcriptome assembly.ConclusionThe analysis of an organism's transcriptome can provide a solid basis for the prediction of biomolecular functions. Using RNA-seq short reads directly, the functional profile of an organism can be reconstructed in a computationally efficient way to provide a draft annotation in cases where the classical genome-based approaches cannot be applied.

Dataset Information

Functional characterization of two secreted SEL1L isoforms capable of exporting unassembled substrate.

Publications

Functional characterization of two secreted SEL1L isoforms capable of exporting unassembled substrate.

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