title: Protection of extraribosomal RPL13a by GAPDH and dysregulation by S-nitrosylation.
abstract: Multiple eukaryotic ribosomal proteins (RPs) are co-opted for extraribosomal "moonlighting" activities, but paradoxically, RPs exhibit rapid turnover when not ribosome-bound. In one illustrative case of a functional extraribosomal RP, interferon (IFN)-γ induces ribosome release of L13a and assembly into the IFN-gamma-activated inhibitor of translation (GAIT) complex for translational control of a subset of inflammation-related proteins. Here we show GAPDH functions as a chaperone, shielding newly released L13a from proteasomal degradation. However, GAPDH protective activity is lost following cell treatment with oxidatively modified low density lipoprotein and IFN-γ. These agonists stimulate S-nitrosylation at Cys(247) of GAPDH, which fails to interact with L13a, causing proteasomal degradation of essentially the entire cell complement of L13a and defective translational control. Evolution of extraribosomal RP activities might require coevolution of protective chaperones, and pathological disruption of either protein, or their interaction, presents an alternative mechanism of diseases due to RP defects, and targets for therapeutic intervention.
authors: Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors: Jie
authors: J
authors: Jia
authors: Abul
authors: A
authors: Arif
authors: Belinda
authors: B
authors: Willard
authors: Jonathan D
authors: JD
authors: Smith
authors: Dennis J
authors: DJ
authors: Stuehr
authors: Stanley L
authors: SL
authors: Hazen
authors: Paul L
authors: PL
authors: Fox
mesh_terms: D005684:Gait / Q000235:genetics; D020868:Gene Silencing; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism*; D022423:Myeloid Cells / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis; D012269:Ribosomal Proteins / Q000235:genetics* / Q000378:metabolism*; D012270:Ribosomes / Q000235:genetics* / Q000378:metabolism*; D020298:U937 Cells; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D008077:Lipoproteins, LDL; D018832:Molecular Chaperones; C402487:RPL13A protein, human; D012269:Ribosomal Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D007371:Interferon-gamma; D046988:Proteasome Endopeptidase Complex