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Authors: Prochnow, Hans
Gollan, Rene
Rohne, Philipp
Hassemer, Matthias
Koch-Brandt, Claudia
Baiersdörfer, Markus
Title: Non-secreted clusterin isoforms are translated in rare amounts from distinct human mRNA variants and do not affect bax-mediated apoptosis or the NF-kappaB signaling pathway
Online publication date: 14-Jul-2022
Year of first publication: 2013
Language: english
Abstract: Clusterin, also known as apolipoprotein J, is expressed from a variety of tissues and implicated in pathological disorders such as neurodegenerative diseases, ischemia and cancer. In contrast to secretory clusterin (sCLU), which acts as an extracellular chaperone, the synthesis, subcellular localization and function(s) of intracellular CLU isoforms is currently a matter of intense discussion. By investigating human CLU mRNAs we here unravel mechanisms leading to the synthesis of distinct CLU protein isoforms and analyze their subcellular localization and their impact on apoptosis and on NF-kappaB-activity. Quantitative PCR-analyses revealed the expression of four different stress-inducible CLU mRNA variants in non-cancer and cancer cell lines. In all cell lines variant 1 represents the most abundant mRNA, whereas all other variants collectively account for no more than 0.34% of total CLU mRNA, even under stressed conditions. Overexpression of CLU cDNAs combined with in vitro mutagenesis revealed distinct translational start sites including a so far uncharacterized non-canonical CUG start codon. We show that all exon 2-containing mRNAs encode sCLU and at least three non-glycosylated intracellular isoforms, CLU1449, CLU21449 and CLU34449, which all reside in the cytosol of unstressed and stressed HEK293 cells. The latter is the only form expressed from an alternatively spliced mRNA variant lacking exon 2. Functional analysis revealed that none of these cytosolic CLU forms modulate caspase-mediated intrinsic apoptosis or significantly affects TNF-alpha-induced NF-kappaB-activity. Therefore our data challenge some of the current ideas regarding the physiological functions of CLU isoforms in pathologies.
DDC: 570 Biowissenschaften
570 Life sciences
Institution: Johannes Gutenberg-Universität Mainz
Department: FB 09 Chemie, Pharmazie u. Geowissensch.
Place: Mainz
Version: Published version
Publication type: Zeitschriftenaufsatz
License: CC BY
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Journal: PLoS one
Pages or article number: e75303
Publisher: PLoS
Publisher place: Lawrence, Kan.
Issue date: 2013
ISSN: 1932-6203
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Publisher DOI: 10.1371/journal.pone.0075303
Appears in collections:DFG-OA-Publizieren (2012 - 2017)

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