Mice deficient in UXT exhibit retinitis pigmentosa-like features via aberrant autophagy activation.
Mice deficient in UXT exhibit retinitis pigmentosa-like features via aberrant autophagy activation.
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UXT 缺陷小鼠通过异常自噬激活表现出视网膜色素变性样特征
DOI：
10.1080/15548627.2020.1796015
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发表时间：
2021-08
期刊：
影响因子：
13.3
通讯作者：
Wang C
中科院分区：
文献类型：
--
作者：
Pan M;Yin Y;Wang X;Wang Q;Zhang L;Hu H;Wang C
UXT（ubiquitously expressed prefoldin like chaperone）是一种小分子分子伴侣样蛋白，广泛表达于人类和小鼠的多种组织中，在视网膜和肾脏中的表达更为丰富。然而，UXT在组织水平上的功能特征在很大程度上是未知的。在这里，我们报道了缺乏UXT的小鼠表现出视网膜变性疾病的显著特征，类似于视网膜色素变性。Uxt的条件性敲除（CKO）可导致小鼠视网膜沿着发生视网膜变性和色素沉着，同时伴有视网膜色素变性相关基因的显著改变，提示UXT可能与视网膜变性疾病相关，其特征与视网膜色素变性相似。CKO组视网膜电图（ERG）反应明显减弱。在uxt CKO视网膜中观察到强烈的退行性特征，包括感光细胞的特异性和进行性减少以及凋亡细胞数量增加。有趣的是，在uxt CKO视网膜中增强了巨自噬/自噬细胞。从机制上讲，我们发现UXT通过调节MTOR（雷帕霉素激酶的机制靶点）（自噬的关键负调节因子）的活性来抑制自噬，从而抑制感光细胞凋亡细胞死亡。相反，UXT的敲除诱导了典型自噬相关基因的稳健表达，并促进了自噬性凋亡和细胞凋亡，最终导致uxt CKO小鼠严重的视网膜变性。综上所述，我们的研究揭示了UXT在预防视网膜变性中的重要作用。UXT的丢失导致超自噬状态，导致大规模视网膜变性。因此，UXT可能是视网膜退行性疾病的重要靶点。缩略语：3-ma：3-甲基腺嘌呤; casp3：胱天蛋白酶3; cko：条件性剔除; erg：视网膜电图; gapdh：甘油醛-3-磷酸脱氢酶; map 1 lc 3b/lc 3b：微管相关蛋白1轻链3; mtor：雷帕霉素激酶的机制靶点; parp：聚（ADP-核糖）聚合酶家族; RNA-Seq：RNA测序; RP：视网膜色素变性; RPS 6 KB 1/S6 K：核糖体蛋白S6激酶B1; SQSTM 1：多价螯合体1; TUNEL：末端脱氧核苷酸转移酶介导的dUTP缺口末端标记; UXT：普遍表达的前折叠蛋白样分子伴侣。
ABSTRACT UXT (ubiquitously expressed prefoldin like chaperone), a small chaperone-like protein, is widely expressed in diverse human and mouse tissues and is more abundant in retina and kidney. However, the functional characterization of UXT at tissue level was largely unknown. Here, we reported that mice deficient in UXT exhibited salient features of retinal degenerative disease, similar to retinitis pigmentosa. Conditional knockout (CKO) of Uxt led to retinal degeneration and pigmentation in mice retina along with significant alterations of retinitis pigmentosa-related genes, which indicated UXT might be associated with retinal degenerative disease sharing key features to retinitis pigmentosa. Consistently, the electroretinogram (ERG) responses were dramatically impaired in uxt CKO retinas. Strong degenerative features were observed in uxt CKO retinas, including specific and progressive reduction of photoreceptor cells and increased numbers of apoptotic cells. Intriguingly, macroautophagic/autophagic flux was enhanced in uxt CKO retina. Mechanistically, we found UXT was indispensable to suppress photoreceptor apoptotic cell death by inhibiting autophagy through regulating the activity of MTOR (mechanistic target of rapamycin kinase), a key negative regulator of autophagy. Conversely, knockdown of UXT induced the robust expression of the canonical autophagy-related genes and boosted autophagic flux and apoptosis, finally resulting in severe retina degeneration in uxt CKO mice. Taken together, our study reveals a vital role of UXT in preventing retina from degeneration. The loss of UXT results in a hyper-autophagic state leading to massive retinal degeneration. Therefore, UXT may be a crucial target for retinal degenerative disease. Abbreviations: 3-ma: 3-methyladenine; casp3: caspase 3; cko: conditional knockout; erg: electroretinogram; gapdh: glyceraldehyde-3-phosphate dehydrogenase; map1lc3b/lc3b: microtubule-associated protein 1 light chain 3; mtor: mechanistic target of rapamycin kinase; parp: poly (adp-ribose) polymerase family; rna-seq: rna sequencing; rp: retinitis pigmentosa; rps6kb1/s6k: ribosomal protein s6 kinase b1; sqstm1: sequestosome 1; tunel: terminal deoxynucleotidyl transferase mediated dutp nick-end labeling; uxt: ubiquitously expressed prefoldin like chaperone.
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