title: Actin cytoskeleton remodeling by the alternatively spliced isoform of PDLIM4/RIL protein.
abstract: RIL (product of PDLIM4 gene) is an actin-associated protein that has previously been shown to stimulate actin bundling by interacting with actin-cross-linking protein α-actinin-1 and increasing its affinity to filamentous actin. Here, we report that the alternatively spliced isoform of RIL, denoted here as RILaltCterm, functions as a dominant-negative modulator of RIL-mediated actin reorganization. RILaltCterm is regulated at the level of protein stability, and this protein isoform accumulates particularly in response to oxidative stress. We show that the alternative C-terminal segment of RILaltCterm has a disordered structure that directs the protein to rapid degradation in the core 20 S proteasomes. Such degradation is ubiquitin-independent and can be blocked by binding to NAD(P)H quinone oxidoreductase NQO1, a detoxifying enzyme induced by prolonged exposure to oxidative stress. We show that either overexpression of RILaltCterm or its stabilization by stresses counteracts the effects produced by full-length RIL on organization of actin cytoskeleton and cell motility. Taken together, the data suggest a mechanism for fine-tuning actin cytoskeleton rearrangement in response to stresses.
authors.affiliation: Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Guryanova
authors.forename: Judith A
authors.initials: JA
authors.lastname: Drazba
authors.forename: Elena I
authors.initials: EI
authors.lastname: Frolova
authors.forename: Peter M
authors.initials: PM
authors.lastname: Chumakov
mesh_terms: D000185:Actinin / Q000235:genetics / Q000378:metabolism; D000199:Actins / Q000235:genetics / Q000378:metabolism*; D017398:Alternative Splicing; D000818:Animals; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D006367:HeLa Cells; D006801:Humans; D060588:LIM Domain Proteins; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism
chemical_list: C526905:ACTN1 protein, human; D000199:Actins; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; C486247:PDLIM4 protein, human; D020033:Protein Isoforms; D000185:Actinin; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D046988:Proteasome Endopeptidase Complex