Roles of STAT3/SOCS3 pathway in regulating the visual function and ubiquitin-proteasome-dependent degradation of rhodopsin during retinal inflammation.
Roles of STAT3/SOCS3 pathway in regulating the visual function and ubiquitin-proteasome-dependent degradation of rhodopsin during retinal inflammation.
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DOI：
10.1074/jbc.m802238200
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发表时间：
2008-09-05
期刊：
影响因子：
--
通讯作者：
Okano H
中科院分区：
文献类型：
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作者：
Ozawa Y;Nakao K;Kurihara T;Shimazaki T;Shimmura S;Ishida S;Yoshimura A;Tsubota K;Okano H
炎性细胞因子引起组织功能障碍。我们以前报道过视网膜炎症下调视紫红质的表达，并通过一种未知的机制损害视觉功能。在这里，我们证明了视紫红质水平是由细胞因子信号转导抑制因子3（SOCS 3），STAT 3激活的负反馈调节器。SOCS 3主要在视网膜感光细胞中表达。在SOCS 3缺陷型视网膜中，视紫红质蛋白水平下降得更快，而且下降幅度比野生型更大。通过视网膜电图测量的视觉功能障碍在视网膜特异性SOCS 3条件性敲除小鼠中延长。视觉功能障碍和视紫红质水平降低均与SOCS 3缺乏增强的STAT 3激活相关。白细胞介素6是视网膜炎症过程中发现的炎性细胞因子之一，在成人视网膜外植体中激活STAT 3并降低视紫红质蛋白。这是通过在体外抑制SOCS 3功能而增强的，表明视紫红质减少在突变小鼠中不是次要效应。有趣的是，在发炎的SOCS 3缺陷型成人视网膜中，视紫红质至少部分通过STAT 3激活加速的泛素-蛋白酶体依赖性降解而在转录后降低，而不是像我们以前报道的那样在发育中的视网膜中转录。STAT 3依赖性E3泛素连接酶Ubr 1负责视紫红质降解，并在SOCS 3缺陷性视网膜炎症中上调。这些结果表明，在野生型动物中，内源性SOCS 3使炎症期间视紫红质的减少最小化。然而，当STAT 3激活超过超过内源性SOCS 3的代偿活性的某个阈值时，视紫红质水平降低。这些发现表明SOCS 3是一种潜在的治疗靶分子，用于在炎症期间保护感光细胞功能。
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.