April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
The Cyclophilin Domain of Ran-binding protein 2 (Ranbp2) Harbors Discriminating Physiological Activities Towards Distinct Retinal Substrates
Author Affiliations & Notes
  • Paulo A Ferreira
    Ophthalmology, Duke University Medical Center, Durham, NC
  • Kyoung-in Cho
    Ophthalmology, Duke University Medical Center, Durham, NC
  • Hemangi Patil
    Ophthalmology, Duke University Medical Center, Durham, NC
  • Eugene Senda
    Ophthalmology, Duke University Medical Center, Durham, NC
  • Jessica Wang
    Ophthalmology, Duke University Medical Center, Durham, NC
  • Haiqing Yi
    Ophthalmology, Duke University Medical Center, Durham, NC
  • Sunny Qiu
    Ophthalmology, Duke University Medical Center, Durham, NC
  • Dosuk Yoon
    Ophthalmology, Duke University Medical Center, Durham, NC
  • Minzhong Yu
    Ophthalmic Research, Cleveland Clinic Foundation, Cleveland, OH
  • Neal S Peachey
    Ophthalmic Research, Cleveland Clinic Foundation, Cleveland, OH
  • Footnotes
    Commercial Relationships Paulo Ferreira, None; Kyoung-in Cho, None; Hemangi Patil, None; Eugene Senda, None; Jessica Wang, None; Haiqing Yi, None; Sunny Qiu, None; Dosuk Yoon, None; Minzhong Yu, None; Neal Peachey, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 414. doi:
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      Paulo A Ferreira, Kyoung-in Cho, Hemangi Patil, Eugene Senda, Jessica Wang, Haiqing Yi, Sunny Qiu, Dosuk Yoon, Minzhong Yu, Neal S Peachey; The Cyclophilin Domain of Ran-binding protein 2 (Ranbp2) Harbors Discriminating Physiological Activities Towards Distinct Retinal Substrates. Invest. Ophthalmol. Vis. Sci. 2014;55(13):414.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: The immunophilins, cyclophilins, catalyze peptidyl cis-trans prolyl-isomerization (PPIase), a rate-limiting step in protein folding and conformational switch in protein function. Cyclophilins are also chaperones. The C-terminal cyclophilin domain (CY) of Ranbp2 acts as a selective chaperone towards M-opsin production in a cell culture system, but its physiological and biological roles in the retina are ill-defined. This study aims at testing the hypothesis that the CY of Ranbp2 harbors non-overlapping PPIase and chaperone activities and discriminating physiological activities towards retinal substrates.

Methods: We generated transgenic mice lacking endogenous Ranbp2 (Ranbp2-/-) and expressing transgenic bacterial artificial chromosomes (BAC) of Ranbp2 with impaired C-terminal chaperone and with (Tg-Ranbp2WT-HA) or without PPIase activities (Tg-Ranbp2R2926A-HA) of its CY domain followed by examination of the transgenic lines with molecular, immunocytochemical and physiological approaches.

Results: Compared to wild-type mice, either transgenic line presents selective deficits in M-opsin biogenesis with its accumulation and aggregation in M- and M/S-cone photoreceptors, but without proteostatic impairment of two novel Ranbp2 cyclophilin partners, the cytokine-responsive effectors, STAT3/STAT5. Stress-induced STAT3 activation and photoreceptor degeneration are also unaffected in retinas of Tg-Ranbp2R2926A-HA::Ranbp2-/-. Conversely, proteomic analyses found the heterogeneous ribonucleic protein A2B1, in which mutations cause multisystem proteinopathy and amyotrophic lateral sclerosis (ALS), is down-regulated post-transcriptionally in inner retinal neurons of only Tg-Ranbp2R2926A-HA::Ranbp2-/- mice. These manifestations are accompanied by the age- and tissue-dependent reductions of diubiquitin and ubiquitylated proteins, increased deubiquitylation activity, and accumulation of the S1 and S5b subunits of the 26S proteasome. These effects are also accompanied by the significant shortening of the implicit times of the scotopic visual evoked potentials.

Conclusions: These results unveil distinct mechanistic and biological links between PPIase and chaperone activities of cyclophilin of Ranbp2 towards proteostasis of selective retinal substrates and with novel therapeutic potential.

Keywords: 450 chaperones • 625 opsins • 659 protein structure/function  
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