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J. Biol. Chem., Vol. 283, Issue 36, 24561-24570, September 5, 2008

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Roles of STAT3/SOCS3 Pathway in Regulating the Visual Function and Ubiquitin-Proteasome-dependent Degradation of Rhodopsin during Retinal Inflammation^*

Yoko Ozawa, Keiko Nakao^¶, Toshihide Kurihara, Takuya Shimazaki, Shigeto Shimmura, Susumu Ishida, Akihiko Yoshimura^||**, Kazuo Tsubota, and Hideyuki Okano¹

From the Departments of Ophthalmology and Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan, ^¶Department of Physiology, Faculty of Medicine, Saitama Medical University, Saitama 350-0495, Japan, ^||Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan, ^**Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan, and Core Research for Evolutional Science and Technology (CREST) and Solution Oriented Research for Science and Technology (SORST), Japan Science and Technology Corporation (JST), Saitaima 332-0012, Japan

Inflammatory cytokines cause tissue dysfunction. We previously reported that retinal inflammation down-regulates rhodopsin expression and impairs visual function by an unknown mechanism. Here, we demonstrate that rhodopsin levels were preserved by suppressor of cytokine signaling 3 (SOCS3), a negative feedback regulator of STAT3 activation. SOCS3 was expressed mainly in photoreceptor cells in the retina. In the SOCS3-deficient retinas, rhodopsin protein levels dropped sooner, and the reduction was more profound than in the wild type. Visual dysfunction, measured by electroretinogram, was prolonged in retina-specific SOCS3 conditional knock-out mice. Visual dysfunction and decreased rhodopsin levels both correlated with increased STAT3 activation enhanced by SOCS3 deficiency. Interleukin 6, one of the inflammatory cytokines found during retinal inflammation, activated STAT3 and decreased rhodopsin protein in adult retinal explants. This was enhanced by inhibiting SOCS3 function in vitro, indicating that rhodopsin reduction was not a secondary effect in the mutant mice. Interestingly, in the inflamed SOCS3-deficient adult retina, rhodopsin decreased post-transcriptionally at least partly through ubiquitin-proteasome-dependent degradation accelerated by STAT3 activation and not transcriptionally as in the developing retina, on which we reported previously. A STAT3-dependent E3 ubiquitin ligase, Ubr1, was responsible for rhodopsin degradation and was up-regulated in the inflamed SOCS3-deficient retinas. These results indicate that in wild-type animals, a decrease in rhodopsin during inflammation is minimized by endogenous SOCS3. However, when STAT3 activation exceeds some threshold beyond the compensatory activity of endogenous SOCS3, rhodopsin levels decrease. These findings suggest SOCS3 as a potential therapeutic target molecule for protecting photoreceptor cell function during inflammation.

Received for publication, March 20, 2008 , and in revised form, June 20, 2008.

^* This study was supported by a grant-in-aid from the Ministry of Education, Science, and Culture (MEXT) of Japan (to Y. O., K. T., and H. O.), a grant from SORST, the Japan Society for Promotion of Science (to H. O.), and the 21st Century COE program of MEXT (to Keio University). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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¹ To whom correspondence should be addressed: 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Tel.: 81-3-5363-3747; Fax: 81-3-3357-5445; E-mail: hidokano{at}sc.itc.keio.ac.jp.

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