July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Ubiquitin-dependent regulation of transducin translocation during light and dark adaptation
Author Affiliations & Notes
  • Takahisa Furukawa
    Institute for Protein Research, Osaka University, Osaka, Japan
  • Taro Chaya
    Institute for Protein Research, Osaka University, Osaka, Japan
  • Ryotaro Tsutsumi
    Institute for Protein Research, Osaka University, Osaka, Japan
  • Leah Varner
    Institute for Protein Research, Osaka University, Osaka, Japan
  • Yamato Maeda
    Institute for Protein Research, Osaka University, Osaka, Japan
  • Footnotes
    Commercial Relationships   Takahisa Furukawa, None; Taro Chaya, None; Ryotaro Tsutsumi, None; Leah Varner, None; Yamato Maeda, None
  • Footnotes
    Support  This work was supported by CREST (AMED), Grant-in-Aid for Scientific Research (18H02593), Young Scientists (17K15548) from the Japan Society for the Promotion of Science (JSPS), The Takeda Science Foundation, The Uehara Memorial Foundation, Senri Life Science Foundation, KANAE Foundation for the Promotion of Medical Science, Suzuken Memorial Foundation, Mitsui Sumitomo Insurance Welfare Foundation and Center for Medical Research and Education, Graduate School of Medicine, Osaka University.
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 1006. doi:
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    • Get Citation

      Takahisa Furukawa, Taro Chaya, Ryotaro Tsutsumi, Leah Varner, Yamato Maeda; Ubiquitin-dependent regulation of transducin translocation during light and dark adaptation. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1006.

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

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Purpose :
Vision in vertebrates begins with light reception by rod and cone photoreceptor cells, which are responsible for low light vision and for daylight and color vision, respectively. While rod photoreceptors become sensitive to light in darkness (dark adaptation), they can also reduce light sensitivity and thus avoid excessive activation, preventing saturation and protecting them from brighter light (light adaptation). However, the underlying regulatory mechanisms remain unclear.

Methods :
In order to identify molecules regulating retinal photoreceptor development and/or function, we screened for genes enriched in photoreceptors using our previously generated microarray data comparing transcripts between control and Otx2 conditional knockout retinas, in which cell fate is converted from photoreceptors to amacrine-like cells. We focused on RetUbE3, which encodes a Cul3 ubiquitin E3 ligase substrate adaptor whose in vivo function has not yet been reported. To investigate roles of the Cul3-RetUbE3 ligase in retinal photoreceptor development and/or function, we generated and analyzed conventional RetUbE3-deficient mice.

Results :
We found that RetUbE3 is predominantly expressed in retinal photoreceptor cells. RetUbE3-deficient mice showed decreased light responses in rod photoreceptors. Loss of RetUbE3 disturbed light- and dark-dependent transducin α-subunit (Tα) translocation, a phenomenon essential for light and dark adaptation. Unc119, an interactor with Tα, is ubiquitinated and degraded by the Cul3-RetUbE3 ligase. Overexpression of Unc119 phenocopied the Tα mislocalization observed in the RetUbE3-deficient retina. Unc119 expression in rod photoreceptors decreased under dark conditions in a RetUbE3-dependent manner. Unc119 is phosphorylated and dephosphorylated by casein kinase 2 (CK2) and calcineurin, a Ca2+-dependent phosphatase, respectively. Unc119 degradation by Cul3-RetUbE3 is suppressed by Unc119 phosphorylation. Notably, inhibition of the Cul3-RetUbE3 ligase or calcineurin activity suppressed light-induced photoreceptor damage.

Conclusions :
Taken together, these results suggest that Cul3-RetUbE3 regulates light- and dark-dependent Tα localization changes in rod photoreceptors through Unc119 ubiquitination and degradation, which is mediated by Unc119 phosphorylation. Our results also suggest potential therapeutic targets for photoreceptor protection.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.


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