Neuroprotection resulting from insufficiency of RANBP2 is associated with the modulation of protein and lipid homeostasis of functionally diverse but linked pathways in response to oxidative stress.
Oxidative stress is a deleterious stressor associated with a plethora of disease and aging manifestations, including neurodegenerative disorders, yet very few factors and mechanisms promoting the neuroprotection of photoreceptor and other neurons against oxidative stress are known. Insufficiency of RAN-binding protein-2 (RANBP2), a large, mosaic protein with pleiotropic functions, suppresses apoptosis of photoreceptor neurons upon aging and light-elicited oxidative stress, and promotes age-dependent tumorigenesis by mechanisms that are not well understood. Here we show that, by downregulating selective partners of RANBP2, such as RAN GTPase, UBC9 and ErbB-2 (HER2; Neu), and blunting the upregulation of a set of orphan nuclear receptors and the light-dependent accumulation of ubiquitylated substrates, light-elicited oxidative stress and Ranbp2 haploinsufficiency have a selective effect on protein homeostasis in the retina. Among the nuclear orphan receptors affected by insufficiency of RANBP2, we identified an isoform of COUP-TFI (Nr2f1) as the only receptor stably co-associating in vivo with RANBP2 and distinct isoforms of UBC9. Strikingly, most changes in proteostasis caused by insufficiency of RANBP2 in the retina are not observed in the supporting tissue, the retinal pigment epithelium (RPE). Instead, insufficiency of RANBP2 in the RPE prominently suppresses the light-dependent accumulation of lipophilic deposits, and it has divergent effects on the accumulation of free cholesterol and free fatty acids despite the genotype-independent increase of light-elicited oxidative stress in this tissue. Thus, the data indicate that insufficiency of RANBP2 results in the cell-type-dependent downregulation of protein and lipid homeostasis, acting on functionally interconnected pathways in response to oxidative stress. These results provide a rationale for the neuroprotection from light damage of photosensory neurons by RANBP2 insufficiency and for the identification of novel therapeutic targets and approaches promoting neuroprotection.
Cho
Kyoung-in
KI
Department of Ophthalmology, Duke University Medical Center, Durham, NC 27710, USA.
Yi
Haiqing
H
Tserentsoodol
Nomingerel
N
Searle
Kelly
K
Ferreira
Paulo A
PA
D000818:Animals; D051838:COUP Transcription Factor I / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D019610:Cytoprotection / Q000528:radiation effects; D005227:Fatty Acids / Q000378:metabolism; D057895:Haploinsufficiency / Q000235:genetics* / Q000528:radiation effects; D006706:Homeostasis / Q000528:radiation effects; D008027:Light; D050356:Lipid Metabolism / Q000528:radiation effects; D051379:Mice; D008954:Models, Biological; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000528:radiation effects; D011485:Protein Binding / Q000528:radiation effects; D020033:Protein Isoforms / Q000378:metabolism; D055351:Retinal Neurons / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D055213:Retinal Pigment Epithelium / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D015398:Signal Transduction / Q000528:radiation effects; D044763:Ubiquitin-Conjugating Enzymes; D057149:Ubiquitinated Proteins / Q000378:metabolism; D000098843:Ubiquitin-Conjugating Enzyme UBC9
D051838:COUP Transcription Factor I; D005227:Fatty Acids; D018832:Molecular Chaperones; D028861:Nuclear Pore Complex Proteins; D020033:Protein Isoforms; D057149:Ubiquitinated Proteins; C094493:ran-binding protein 2; D002784:Cholesterol; D044763:Ubiquitin-Conjugating Enzymes; D000098843:Ubiquitin-Conjugating Enzyme UBC9