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.
Abstract
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.
Type
Journal articleSubject
AnimalsCOUP Transcription Factor I
Cholesterol
Cytoprotection
Fatty Acids
Haploinsufficiency
Homeostasis
Light
Lipid Metabolism
Mice
Models, Biological
Molecular Chaperones
Nuclear Pore Complex Proteins
Oxidative Stress
Protein Binding
Protein Isoforms
Retinal Neurons
Retinal Pigment Epithelium
Signal Transduction
Ubiquitin-Conjugating Enzymes
Ubiquitinated Proteins
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https://hdl.handle.net/10161/4182Published Version (Please cite this version)
10.1242/dmm.004648Publication Info
Cho, Kyoung-in; Yi, Haiqing; Tserentsoodol, Nomingerel; Searle, Kelly; & Ferreira,
Paulo A (2010). 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. Dis Model Mech, 3(9-10). pp. 595-604. 10.1242/dmm.004648. Retrieved from https://hdl.handle.net/10161/4182.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Paulo Alexandre Ferreira
Associate Professor in Ophthalmology
The long-term goal of our research program is twofold. The first is to understand
the interplay between intracellular signaling, intracellular trafficking and proteostasis in
health and disease; the second is to uncover molecular players and mechanisms partaking
in such processes that are amenable to therapeutic intervention in a variety of disease
states. Presently, our research efforts are centered on dissecting the roles of two
disease-associated protein interactomes assembled by the Ran

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